Patent Publication Number: US-2006004036-A1

Title: Sigma-2 receptor agonists and their use in the treatment of HIV infection

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
      This application is a continuation-in-part of PCT Application PCT/U.S. 2004/000739, filed Jan. 14, 2004 (pending); this application claims priority to PCT Application PCT/US2004/000739, filed Jan. 14, 2004, and U.S. Patent Application Ser. No. 60/440,367, filed on Jan. 16, 2003, both of which applications are hereby incorporated by reference in their entirety. 
    
    
     STATEMENT OF GOVERNMENTAL INTEREST  
      Aspects of the invention were funded by the United States National Institutes of Health. The United States Government has certain rights to this invention. 
    
    
     FIELD OF THE INVENTION  
      This invention relates to sigma-2 receptor agonists and their use in the treatment of immunodeficiency virus infections, especially human immunodeficiency virus (HIV) infections.  
     BACKGROUND OF THE INVENTION  
      The human immunodeficiency virus (HIV) is a pathogenic retrovirus (Varmus, H. (1988) “R ETROVIRUSES ,” Science 240:1427-1439; Cowley S. (2001) “T HE  B IOLOGY  O F  HIV I NFECTION ” Lepr Rev. 72(2):212-20). It is the causative agent of acquired immune deficiency syndrome (AIDS) and related disorders (Gallo, R. C. et al. (1983) “Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS),” Science 220(4599):865-7; Barre-Sinoussi, F. et al. “I SOLATION  O F  A T-L YMPHOTROPIC  R ETROVIRUS  F ROM  A P ATIENT  A T  R ISK  F OR  A CQUIRED  I MMUNE  D EFICIENCY  S YNDROME  (AIDS), (1983) Science 220:868-870; Gallo, R. et al. (1984) “F REQUENT  D ETECTION  A ND  I SOLATION  O F  C YTOPATHIC  R ETROVIRUSES  (HTLV-III) F ROM  P ATIENTS  W ITH  AIDS A ND  A T  R ISK  F OR  AIDS,” Science 224:500-503; Teich, N. et al. (1984) “RNA T UMOR  V IRUSES ,” Weiss, R. et al. (eds.) Cold Spring Harbor Press (NY) pp. 949-956). HIV acts to compromise the immune system of infected individuals by targeting and infecting the CD-4 +  T lymphocytes that would otherwise be the major proponents of the recipient&#39;s cellular immune system response (Dalgleish, A. et al. (1984) “T HE  CD4 (T4) A NTIGEN  I S  A N  E SSENTIAL  C OMPONENT  O F  T HE  R ECEPTOR  F OR  T HE  AIDS R ETROVIRUS ,” Nature 312: 767-768, Maddon et al. (1986) “T HE  T4 G ENE  E NCODES  T HE  AIDS V IRUS  R ECEPTOR  A ND  I S  E XPRESSED  I N  T HE  I MMUNE  S YSTEM  A ND  T HE  B RAIN ,” Cell 47:333-348; McDougal, J. S. et al. (1986) “B INDING  O F  HTLV-III/LAV T O  T4+ T C ELLS  B Y  A C OMPLEX  O F  T HE  110 K V IRAL  P ROTEIN  A ND  T HE  T4 M OLECULE ,” Science 231:382-385). HIV infection is pandemic and HIV-associated diseases represent a major world health problem.  
      Attempts to treat HIV infection have focused on the development of drugs that disrupt the viral infection and replication cycle (see, Mitsuya, H. et al. (1991) “T ARGETED  T HERAPY  O F  H UMAN  I MMUNODEFICIENCY  V IRUS -R ELATED  D ISEASE ,” FASEB J. 5:2369-2381). Such intervention could potentially inhibit the binding of HIV to cell membranes, the reverse transcription of the HIV RNA genome into DNA, the exit of the virus from the host cell and infection of new cellular targets, or inhibition of viral enzymes (see, U.S. Pat. No. 6,475,491). Thus, for example, soluble CD4 has been developed in an effort to competitively block the binding of HIV to lymphocytes (Smith, D. H. et al. (1987) “B LOCKING  O F  HIV-1 I NFECTIVITY  B Y  A S OLUBLE , S ECRETED  F ORM  O F  T HE  CD4 A NTIGEN ,” Science 238:1704-1707; Schooley, R. et al. (1990) “R ECOMBINANT  S OLUBLE  CD4 T HERAPY  I N  P ATIENTS  W ITH  T HE  A CQUIRED  I MMUNODEFICIENCY  S YNDROME  (AIDS) A ND  AIDS-R ELATED  C OMPLEX . A P HASE  I-II E SCALATING  D OSAGE  T RIAL ,” Ann. Int. Med. 112:247-253; Kahn, J. O. et al. (1990) “T HE  S AFETY  A ND  P HARMACOKINETICS  O F  R ECOMBINANT  S OLUBLE  CD4 ( R CD4) I N  S UBJECTS  W ITH  T HE  A CQUIRED  I MMUNODEFICIENCY  S YNDROME  (AIDS) A ND  AIDS-R ELATED  C OMPLEX . A P HASE  I S TUDY ,” Ann. Int. Med. 112:254-261; Yarchoan, R. et al. (1989) Proc. V th  Int. Conf. on AIDS, p564, MCP 137).  
      Likewise, drugs such as 2′,3′-dideoxynucleoside analogs (e.g., azidothymidine (AZT), dideoxyinosine, dideoxycytidine, and d4thymidine have been developed to target the virus&#39; reverse-transcriptase (Yarchoan, R. et al. (1989) “C LINICAL  P HARMACOLOGY  O F  3′-A ZIDO -2′,3′-D IDEOXYTHYMIDINE  (Z IDOVUDINE ) A ND  R ELATED  D IDEOXYNUCLEOSIDES ,” N Engl J. Med. 321(11):726-38). Recently, inhibitors of the HIV protease have been identified and used to treat HIV infection (see, U.S. Pat. No. 6,472,404; Todd, S. et al. (2000) “HIV P ROTEASE  A S  A T ARGET  F OR  R ETROVIRUS  V ECTOR -M EDIATED  G ENE  T HERAPY ,” Biochim Biophys Acta. 1477(1-2):168-88).  
      Unfortunately, although considerable effort has been expended to design effective therapeutics, no curative anti-retroviral drugs against AIDS currently exist. All available therapies are marred by substantial adverse side effects, and by the capacity of HIV to rapidly mutate into forms that are refractive to treatment (Miller, V. et al. (2001) M UTATIONAL  P ATTERNS  I N  T HE  HIV G ENOME  A ND  C ROSS -R ESISTANCE  F OLLOWING  N UCLEOSIDE  A ND  N UCLEOTIDE  A NALOGUE  D RUG  E XPOSURE ,” Antivir Ther. 6 Suppl 3:25-44; Lerma, J. G. et al. (2001) “R ESISTANCE  O F  H UMAN  I MMUNODEFICIENCY  V IRUS  T YPE  I T O  R EVERSE  T RANSCRIPTASE  A ND  P ROTEASE  I NHIBITORS : G ENOTYPIC  A ND  P HENOTYPIC  T ESTING ,” J Clin Virol. 21(3): 197-212; O&#39;Brien, W. A. (2000) “R ESISTANCE  A GAINST  R EVERSE  T RANSCRIPTASE  I NHIBITORS ,” Clin Infect Dis. 30 Suppl 2:S185-92; Wain-Hobson, S. (1996) “R UNNING  T HE  G AMUT  O F  R ETROVIRAL  V ARIATION ,” Trends Microbiol. 4(4):135-41; Lange J. (1995) “C OMBINATION  A NTIRETROVIRALTHERAPY . B ACK  T O  T HE  F UTURE ,” Drugs. 49 Suppl 1:32-40). Thus, a continuing need exists for safe and effective anti-HIV therapeutics. The present invention is directed to this and other goals.  
      Sigma receptors are unique drug binding sites with pharmacological profiles and potential functions that are unrelated to other known receptors (Walker, J. M. et al. (1990) “S IGMA  R ECEPTORS : B IOLOGY  A ND  F UNCTION ,” Pharmacol. Rev. 42:355-402; Su, T.-P. (1993) “D ELINEATING  B IOCHEMICAL  A ND  F UNCTIONAL  P ROPERTIES  O F  S IGMA  R ECEPTORS :  EMERGING  C ONCEPTS ,” Crit. Rev. Neurobiol. 7:187-203; Bowen, W. D. (2000) “S IGMA  R ECEPTORS : R ECENT  A DVANCES  A ND  N EW  C LINICAL  P OTENTIALS ,” Pharm. Acta Helv. 74(2-3):211-8). Two pharmacologically defined subclasses of sigma-receptor (sigma-1 and sigma-2) are now widely accepted (Hellewell, S. B. et al. (1990) “A S IGMA - LIKE  B INDING  S ITE  I N  R AT  P HEOCHROMOCYTOMA  (PC12) C ELLS : D ECREASED  A FFINITY  F OR  (+)- BENZOMORPHANS AND LOWER MOLECULAR WEIGHT SUGGEST A DIFFERENT SIGMA RECEPTOR FORM FROM THAT IN GUINEA PIG BRAIN ,” Brain Res. 527: 244-253; Quirion, R. et al. (1992) “A  PROPOSAL FOR THE CLASSIFICATION OF SIGMA BINDING SITES ,” Trends Pharmacol. Sci. 13: 85-86). Sigma receptors are expressed in many cell types and tissues, including those of the nervous, immune, and endocrine systems (Wolfe, S. A. et al. (1989) “S IGMA  R ECEPTORS  I N  E NDOCRINE  O RGANS —I DENTIFICATION , C HARACTERIZATION , A ND  A UTORADIOGRAPHIC  L OCALIZATION  I N  R AT  P ITUITARY , A DRENAL , T ESTIS , A ND  O VARY ,” Endocrinol. 124:1160-1172; Wolfe, S. A. et al. (1992) “S IGMA  R ECEPTORS  I N  T HE  B RAIN -E NDOCRINE -I MMUNE  A XIS ,” In: J. M. Kamenka and E. F. Domino (eds.), M ULTIPLE  S IGMA  A ND  PCP R ECEPTOR  L IGANDS : M ECHANISMS  F OR  N EUROMODULATION  A ND  N EUROPROTECTION? , pp. 115-126, Ann Arbor: NPP Books; Hellewell, S. B. et al. (1994) “R AT  L IVER  A ND  K IDNEY  C ONTAIN  H IGH  D ENSITIES  O F  S IGMA -1 A ND  S IGMA -2 R ECEPTORS : C HARACTERIZATION  B Y  L IGAND  B INDING  A ND  P HOTOAFFINITY  L ABELING ,” Eur. J. Pharmacol.—Mol. Pharmacol. Sect. 268:9-18) Furthermore, sigma receptors are highly expressed in tumor cell lines derived from these tissues (Vilner, B. J. et al. (1995) “S IGMA -1 A ND  S IGMA -2 R ECEPTORS  A RE  E XPRESSED  I N  A W IDE  V ARIETY  O F  H UMAN  A ND  R ODENT  T UMOR  C ELL  L INES ,” Cancer Res. 55:408-413) and are upregulated in rapidly proliferating cells (Wheeler, K. T. et al. (2000) “S IGMA -2  RECEPTORS AS A BIOMARKER OF PROLIFERATION IN SOLID TUMOURS .” Br. J. Cancer 82(6): 1223-32).  
      Sphingolipids include classes of lipids that constitute major structural components of specialized domains in cell membranes (Brown, D. A. et al. (2000) “S TRUCTURE  A ND  F UNCTION  O F  S PHINGOLIPID - A ND  C HOLESTEROL -R ICH  M EMBRANE  R AFTS ,” J. Biol. Chem. 275:17221-17224) Additionally, certain sphingolipids and sphingolipid-derived compounds have been found to affect cell growth and proliferation, as well as cell death (Kolesnick, R. N. et al. (1998) “R EGULATION  O F  C ERAMIDE  P RODUCTION  A ND  A POPTOSIS ,”Annu. Rev. Physiol. 60:643-665). Sigma-2 receptor activation has an effect on cellular proliferation and survival which may be mediated by sphingolipids.  
      Compounds that activate the sigma-2 receptor (i.e., “sigma-2 agonists”) have been identified (PCT Publication No. WO 01/85153; PCT Publication No. WO 01/80905; PCT Publication No. WO 97/34892; PCT Publication No. WO 97/30038; PCT Publication No. WO 96/05185; European Patent Publication No. EP 0881220A1; U.S. Pat. No. 6,015,543; U.S. Pat. No. 5,993,777; U.S. Pat. No. 5,919,934; U.S. Pat. No. 5,969,138; U.S. Pat. No. 5,911,970.  
      Some sigma-2 receptor agonists have been found to increase cellular ceramide production. Such compounds are generally recognized as cytotoxic, and are used to potentiate the use of antineoplastic agents in the treatment of cancer cells (see, PCT Publication No. WO 01/85153; Crawford, K. W. et al. (2002) “S IGMA -2 R ECEPTOR  A GONISTS  A CTIVATE  A N OVEL  A POPTOTIC  P ATHWAY  A ND  P OTENTIATE  A NTINEOPLASTIC  D RUGS  I N  B REAST  T UMOR  C ELL  L INES ,” Cancer Res 62(1):313-22). The use of sigma-2 agonists to regulate sphingolipid levels is disclosed in Crawford, K. W. et al. (2002) (“SIGMA-2 R ECEPTORS  R EGULATE  C HANGES  I N  S PHINGOLIPID  L EVELS  I N  B REAST  T UMOR  C ELLS ,” Eur. J. Pharmacol. 443:207-209), Crawford, K. W. et al. (2001) (“S IGMA -2 R ECEPTORS  M AY  A CTIVATE  S PHINGOLIPID -C ERAMIDE  N-D EACYLASE  (SCD ASE ) A S  A M ECHANISM  T O  R EGULATE  C ELL  G ROWTH ,” Soc. Neurosci. Abstr. 27:948); Bowen, W. D. et al. (2000) (“A CTIVATION  O F  S IGMA -2 R ECEPTORS  C AUSES  C HANGES  I N  C ERAMIDE  L EVELS  I N  N EURONAL  A ND  N ON -N EURONAL  C ELL  L INES ,” Soc. Neurosci. Abstr. 26:601); and Crawford, K. W. et al. (2001) (“E VIDENCE  F OR  S IGMA -2 R ECEPTOR  C ONTROL  O F  S PHINGOLIPID  S IGNALING  V IA  S PHINGOLIPID  C ERAMIDE  N-D EACYLASE  (SCD ASE ) I N  B REAST  T UMOR  C ELLS ,” P ROC . AACR 42:3659).  
     SUMMARY OF THE INVENTION  
      The ability of HIV to infect lymphocytes requires sphingomyelin, compounds that attenuate sphingomyelin production (or its presence in the cellular membranes) have the potential to inhibit or prevent immunodeficiency virus infection, especially human immunodeficiency virus (HIV) infection. The present invention particularly relates to sigma-2 receptor agonists and their use in the treatment of human immunodeficiency virus infections. The invention especially concerns sigma-2 agonists, especially CB-184 and its analogues, that decrease membrane sphingomyelin content when provided to recipient cells, and inhibit HIV replication and infection.  
      In detail, the invention concerns a method for treating actual or potential infection by an immunodeficiency virus in a mammal, wherein the method comprises administering to the mammal a therapeutically or prophylactically effective amount of a sigma-2 agonist.  
      The invention particularly concerns the embodiment of such method wherein the method is a method for treating actual infection by an immunodeficiency virus, and the administered amount of the sigma-2 agonist is a therapeutically effective amount.  
      The invention further concerns the embodiments of such methods wherein the method is a method for treating potential infection by an immunodeficiency virus, and the administered amount of the sigma-2 agonist is a prophylactically effective amount.  
      The invention particularly concerns the embodiments of such methods wherein the mammal is a human and the immunodeficiency virus is HIV, wherein the mammal is a simian and the immunodeficiency virus is SIV, and wherein the mammal is a feline and the immunodeficiency virus is a feline immunodeficiency virus.  
      The invention particularly concerns the embodiments of such methods wherein the sigma-2 agonist is a sigma-2 selective agonist, and especially wherein the sigma-2 agonist is a (+)-5,8-disubstituted morphan-7-one, or salt thereof. The invention particularly concerns the embodiments of such methods wherein the (+)-5,8-disubstituted morphan-7-one is CB-184 {(+)-1R,5R-E-8-(3,4-dichlorobenzylidene)-5-(3-hydroxyphenyl)-2-methylmorphan-7-one}.  
      The invention further provides the embodiment of the above-described methods wherein the method additionally comprises providing the mammal with a therapeutically effective amount of a drug that disrupts the life cycle of the virus, a drug that impairs the binding of the virus to a target cell, or a nucleotide analog.  
      The invention further provides the embodiment of the above-described methods wherein the method additionally comprises providing the mammal with a prophylactically effective amount of a drug that disrupts the life cycle of the virus, a drug that impairs the binding of the virus to a target cell, or a nucleotide analog.  
      The invention further provides an anti-immunodeficiency virus composition, the composition comprising an amount of a sigma-2 agonist effective for treating an actual or potential immunodeficiency virus infection in a mammal.  
      The invention particularly concerns the embodiment of such anti-immunodeficiency virus composition wherein the sigma-2 agonist is a sigma-2 selective agonist. The invention further concerns the embodiment of such anti-immunodeficiency virus composition wherein the sigma-2 agonist is a (+)-5,8-disubstituted morphan-7-one, or a salt thereof. The invention particularly concerns the embodiment of such anti-immunodeficiency virus composition wherein the (+)-5,8-disubstituted morphan-7-one is CB-184 {(+)-1R,5R-E-8-(3,4-dichlorobenzylidene)-5-(3-hydroxyphenyl)-2-methylmorphan-7-one}.  
      The invention additionally concerns the embodiments of the above-described anti-immunodeficiency virus compositions wherein the composition additionally comprises a drug that disrupts the life cycle of the virus, a drug that impairs the binding of the virus to a target cell, or a nucleotide analog. The invention particularly concerns the embodiment of such anti-immunodeficiency virus compositions wherein the virus is HIV, and the mammal is a human. 
    
    
     BRIEF DESCRIPTION OF THE FIGURES  
       FIG. 1  shows the effect of sigma-2 agonists on sphingomyelin levels in H9 lymphocytes incubated in the presence of CB-184 or Haldol.  
       FIG. 2  shows the effect of CB184, CB64D, BD737 and haldol on HIV infection.  
       FIG. 3  shows the effect of compound AC-927 and CB-184 on LuSIV cell susceptibility to HIV infection using the lucerferase assay.  
       FIG. 4  shows the interaction between AC-927 and CB-184 on HIV infection.  
       FIG. 5  shows the interaction between compound AC-927 and CB-184 on HIV infection. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
      The present invention derives in part from the discovery that compounds that activate cellular sigma-2 receptors are associated with a diminished presence of sphingomyelin in the cellular membrane. Although such compounds have generally been recognized as cytotoxic, one aspect of the present invention relates to the recognition that sub-cytotoxic doses of such compounds inhibit HIV replication. Notably, because such compounds do not target viral protein, the invention surmounts the capacity of HIV to mutate into forms that are resistant to anti-viral agents. Thus, the invention provides a potential treatment for blocking HIV infection that would overcome the most significant challenge encountered in the use of alternative HIV treatment regimes.  
      This invention involves the use of a sigma-2 agonist for treating patients suffering from HIV infection. As used herein, a “sigma-2 agonist” is a compound that activates cellular sigma-2 receptors. Any ligand with sigma-2 agonistic activity can be used in accordance with the present invention.  
      A preferred sigma-2 agonist is one which exhibits a greater binding preference for the sigma-2 receptor relative to the sigma-1 receptor and, thus, is defined as a “sigma-2 selective” agonist. More preferred is a sigma-2 selective agonist that exhibits about a 25-fold or greater binding preference for the sigma-2 receptor relative to the sigma-1 receptor. A still more preferred sigma-2 selective agonist exhibits about a 50-fold or greater selectivity for the sigma-2 receptor relative to the sigma-1 receptor, and a most preferred sigma-2 selective agonist exhibits about a 100-fold or greater selectivity for the sigma-2 receptor relative to the sigma-1 receptor.  
      Particularly preferred sigma-2 agonists are disclosed in U.S. Pat. Nos. 5,130,330, 5,346,908, 5,571,832, 5,571,832, 5,656,625, 5,656,625, 5,679,673, 5,679,679, 5,679,679, 5,739,158, 5,856,318 and 6,310,064. Thus, preferred compounds include compounds of the formula:  
                 
 
 wherein R 1  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy, cyanoalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of R 4  through R 11  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 4  and R 5  may be taken; together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein R 10  and R 11  may be taken together to form oxo; wherein each of n and m is a number selected from one through four; wherein each of p and q is a number selected from zero through five; wherein each of X and Z is independently selected from  
                 
 
 wherein R 12  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R 13  through R 16  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds consists of those compounds wherein R 1  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl and carboxyalkyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy and cyanoalkyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of R 4  through R 11  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of n and m is a number selected from one through four; wherein each of p and q is a number selected from zero through five; wherein X is selected from  
                 
          wherein Z is selected from O,  
                 
 
 wherein R 12  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R 13  through R 16  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof. 
       

      A more preferred family of such compounds consists of those compounds wherein R 1  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy-lower alkyl, halo-lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy-lower alkyl, phenyl-lower alkyl, phenyl, lower alkenyl-lower alkyl, lower alkynyl-lower alkyl and carboxy lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, carboxy lower alkyl, lower alkanoyl, lower alkoxycarbonyl, carboxy and cyano lower alkyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of R 4  through R 11  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, phenyl lower alkoxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanol, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of n and m is a number selected from one through four; wherein each of p and q is a number selected from zero through five; wherein X is selected from  
                 
          wherein Z is selected from O,  
                 
 
 wherein R 12  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl, phenyl lower alkyl, heteroaryl, lower alkoxy lower alkyl, hydroxy lower alkyl, lower alkanoyl, phenylalkanoyl, benzoyl, amino lower alkyl, mono lower alkylamino lower alkyl and di lower alkylamino lower alkyl; wherein each of R 13  through R 16  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, pheny lower alkyl, phenyl, lower alkoxy, phenyl lower alkoxy, phenoxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, halo, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl and lower alkanoyl; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, naphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
       

      A more highly preferred family of such compounds consists of those compounds wherein R 1  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl lower alkyl and lower alkynyl lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, lower alkanoyl and lower alkoxycarbonyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of R 4  through R 11  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy, phenoxy, benzyloxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of n and m is a number selected from one through four; wherein each of p and q is a number selected from zero through five; wherein X is selected from  
                 
          wherein Z is selected from O,  
                 
 
 wherein R 12  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl, benzyl, lower alkoxy lower alkyl and hydroxy lower alkyl; wherein each of R 13  through R 16  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy, benzyloxy, phenoxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl and halo; wherein A :is selected from phenyl, naphthyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
       

      A family of such compounds of particular interest are compounds embraced by the formula:  
                 
 
 wherein R 1  is selected from hydrido, lower alkyl, cycloalkylalkyl of four to six carbon atoms and lower alkenyl lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido and lower alkyl; wherein each of R 4  through R 7 , R 10  and R 11  is independently selected from hydrido, hydroxy, lower alkyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein n is a number selected from four through six; wherein p is a number selected from zero through four; wherein q is a number selected from three through five; wherein A is selected from phenyl, naphthyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, lower alkoxy, halo, halo lower alkyl, amino, mono lower alkylamino and di lower alkylamino; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of compounds wherein R 1  is selected from hydrido, methyl, ethyl, propyl, cyclopropylmethyl, allyl and dimethylallyl; wherein each of R 2  and R 3  is independently selected from hydrido, methyl, ethyl and propyl; wherein each of R 4  through R 7 , R 10  and R 11  is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein n is a number selected from four or five; wherein p is a number selected from zero through two; wherein q is a number selected from three or four; wherein A is phenyl or naphthyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamine; or a pharmaceutically acceptable salt thereof.  
      Compounds of the following formula are particularly preferred:  
                 
 
 wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 5  alkyl, C 3 -C 8  cycloalkyl or C 4 -C 8  cycloalkylalkyl with the proviso that when R1 is methyl, than p is not 1; R 2 , R 3 , R 4  and R 5  are hydrogen; and A is phenyl and wherein A may be further substituted with one or more halo substituents. 
 
      Particularly preferred examples of such compounds include: 
      (±)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)-cyclohexylamine;     1S,2R-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)-cyclohexylamine;     1R,2S-(−)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)-cyclohexylamine;     1S,2R-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)cyclohexylamine;     1R,2S(−)-cis-N-[2-(3,4-dichlorophenyl) ethyl]N-ethyl-2-(1-pyrrolidinyl)cyclohexylamine;     1S,2R-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-(1-propyl)-2-(1-pyrrolidinyl)cyclohexylamine;     1R,2S-(−)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-(1-propyl)-2-(1-pyrrolidinyl)cyclohexylamine;     1S,2R-(+)-cis-N-[2-(3,4,-dichlorophenyl)ethyl]-N-cyclopropylmethyl-1-(1-pyrrolidinyl)cyclohexylamine;     1R,2S-(−)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-cyclopropylmethyl-2-(1-pyrrolidinyl)-cyclohexylamine; and     (±)-cis-N-[2-(3,4-dichlorophenyl)methyl]-N-methyl-2-(1-pyrrolidinyl)-cyclohexylamine;    

      BD737 is a particularly preferred sigma-2 agonist. BD737 is 1S,2R-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)-cyclohexylamine (Bowen, W. D. et al. (1992) “C HARACTERIZATION  O F  T HE  E NANTIOMERS  O F CIS -N-[2-(3,4- DICHLOROPHENYL ) ETHYL ]-N-M ETHYL -2-(1- PYRROLIDINYL )  CYCLOHEXYLAMINE  (BD737  AND  BD738): N OVEL  C OMPOUNDS  W ITH  H IGH  A FFINITY , S ELECTIVITY , A ND  B IOLOGICAL  E FFICACY  A T  S IGMA  R ECEPTORS ,” J. Pharmacol. Exp. Ther. 262:32-40; Vilner, B. J. et al. (2000) “M ODULATION  O F  C ELLULAR  C ALCIUM  B Y  S IGMA -2 R ECEPTORS : R ELEASE  F ROM  I NTRACELLULAR  S TORES IN  H UMAN  SK-N-SH N EUROBLASTOMA  C ELLS ,” J. Pharmacol. Exp. Ther. 292(3):900-11).  
      Additional examples of sigma-2 agonists include compounds of the formula:  
                 
 
 wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R3 and R 8  through R 13  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight Ting carbons; wherein R 8  and R 9  may be taken together to form oxo; wherein R 10  and R 11  may be taken together to form oxo; wherein m is an integer from 2-4 and n and p are integers of from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R 15  and R 16  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein each of R 17  and R 18  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxyl aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds consists of those compounds wherein each of R 1  R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 10  and R 11  may be taken together to form oxo; wherein m is an integer from 2-4 and n and p are integers of from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl, aralkanoyl and aroyl; wherein each of R 15  through R 18  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of those compounds wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms, phenylloweralkyl, phenyl, loweralkoxyloweralkyl, haloloweralkyl; hydroxyloweralkyl, carboxy, carboxyloweralkyl, loweralkanyl, loweralkenyl, loweralkynyl; wherein R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy, phenoxy, phenylloweralkoxy, loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl, cyano, amino, monoloweralkylamino, diloweralkylamino, carboxy, carboxyloweralkyl, loweralkanoyl, loweralkenyl and loweralkynyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 10  and R 11  may be taken together to form oxo; wherein m is an integer from 2-4 and n and p are integers of from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl, phenyl lower alkyl, heteroaryl, lower alkanoyl, phenylalkanoyl, benzoyl, amino lower alkyl, mono lower alkyl-amino lower alkyl and di lower alkylamino-lower alkyl; wherein each of R 15  and R 16  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, pheny lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, halo, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl and lower alkanoyl; wherein each of R 17  and R 18  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, halo, cyano, carboxy, carboxy lower alkyl and lower alkanoyl; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, naphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A more highly preferred family of such compounds consists of those compounds wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl, and lower alkynyl; wherein R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy, phenoxy, benzyloxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 10  and R 11  may be taken together to form oxo; wherein m is an integer from 2-4 and n and p are integers of from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl and benzyl; wherein each of R 15  through R 18  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, hydroxy lower alkyl and halo; wherein A is selected from phenyl, naphthyl, benzo[b]thienyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A family of compounds of particular interest within Formula I are compounds embraced by the formula:  
                 
 
 wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, benzyl and halo lower alkyl; wherein R 2 , R 3  and R 8  through R 11  is independently selected from hydrido, hydroxy, lower alkyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein n is an integer of from four to six; wherein m is an integer of from two to four; wherein A is selected from phenyl, naphthyl, benzothienyl, benzofuranyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, lower alkoxy, halo, halo lower alkyl, amino, mono lower alkylamino and di lower alkylamino; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of compounds wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, methyl, ethyl, propyl, benzyl, and halo lower alkyl, wherein R 2 , R 3  and R 8  through R 11  is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein n is a number selected from 4 or 5; wherein in is an integer of from two or three; wherein A is phenyl or naphthyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamino; or a pharmaceutically acceptable salt thereof.  
      The following specific compounds are particularly preferred: 
      2-[2-(3,4-dichlorophenyl)ethyl]-2,5-diazabicyclo[3.0.4]nonane     2-[2-(3-benzothienyl)ethyl]-2,5-diazabicyclo[3.0.4]nonane     2-[2-naphthylethyl]-2,5-diazabicyclo[3.0.4]nonane     2-[2-(3,4-dichlorophenyl)ethyl]-2,5-diazabicyclo[4.0.4]decane     2-[2-(3-benzothienyl)ethyl]-2,5-diazabicyclo[4.0.4]decane     2-[2-naphthylethyl]-2,5-diazabicyclo[4.0.4]decane    

      Additional examples of sigma-2 agonists include compounds of the formula:  
                 
 
 wherein each of R 1 , R 10  and R 11  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy, cyanoalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 4  through R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein one of R 10  or R 11  together with one of R 6  or R 7 , or together with one of R 8  or R 9 , form a heterocyclic ring moiety which includes the nitrogen atom to which R 10  and R 11  are attached, said ring moiety having from five to ten ring members; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds consists of those compounds wherein each of R 1 , R 10  and R 11  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl and carboxyalkyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy and cyanoalkyl; wherein each of R 4  through R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein one of R 10  and R 11  together with one of R 6  and R 7 , or together with one of R 8  and R 9 , form a heterocyclic ring moiety which includes the nitrogen atom to which R 10  and R 11  are attached, said ring moiety having from five to ten ring members; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof.  
      A more preferred family of such compounds consists of those compounds wherein each of R 1 , R 10  and R 11  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl and carboxy lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, carboxy lower alkyl, lower alkanoyl, lower alkoxycarbonyl, carboxy and cyano lower alkyl; wherein each of R 4  through R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein one of R 10  and R 11  together with one of R 6  and R 7 , or together with one of R 8  and R 9 , form a heterocyclic ring moiety which includes the nitrogen atom to which R 10  and R 11  are attached, said ring moiety having from five to ten ring members; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, natphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof.  
      A more highly preferred family of such compounds consists of those compounds wherein each of R 1 , R 10  and R 11  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl lower alkyl and lower alkynyl lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, lower alkanoyl and lower alkoxycarbonyl; wherein each of R 4  through R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein one of R 10  and R 11  together with one of R 6  and R 7 , or together with one of R 8  and R 9 , form a heterocyclic ring moiety which includes the nitrogen atom to which R 10  and R 11  are attached, said ring moiety having from five to ten ring members; wherein A is selected from phenyl, naphthyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof.  
      A preferred sub-class of such compounds are compounds represented by the formula:  
                 
 
 wherein each of R 1  and R 10  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy, cyanoalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 4  through R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein n is an integer of from 2 to 7; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds are those compounds wherein R 1  and R 10  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl and carboxyalkyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy and cyanoalkyl; wherein each of R 4  through R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof.  
      A more preferred family of such compounds are those compounds wherein R 1  and R 10  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl and carboxy lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, carboxy lower alkyl, lower alkanoyl, lower alkoxycarbonyl, carboxy and cyano lower alkyl; wherein each of R 4  through R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, naphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof.  
      A more highly preferred family of such compounds are those compounds wherein R 1  and R 10  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl lower alkyl and lower alkynyl lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, lower alkanoyl and lower alkoxycarbonyl; wherein each of R 4  through R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein A is selected from phenyl, naphthyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. Compounds of particular interest that fall within the scope of such formula include: 
      3-[N-(3,4-dichlorophenyl)ethyl]-N-(methyl)amino]-1-(methyl)piperidine     3-[N-(3,4-dichlorophenyl)ethyl]-N-(methyl)amino]-1-(methyl)homopiperidine     3-[N-(3,4-dichlorophenyl)ethyl]-N-(methyl)amino]-1-(methyl)pyrrolidine     3-[N-(3-benzothienyl)ethyl]-N-(methyl)amino]-1-(methyl)piperidine     3-[N-(3-benzothienyl)ethyl]-N-(methyl)amino]-1-(methyl)homopiperidine     3-[N-(3-benzothienyl)ethyl]-N-(methyl)amino]-1-(methyl)pyrrolidine     3-[N-(2-[2-napthyl]ethyl)]-N-(methyl)amino]-1-(methyl)piperidine     3-[N-(2-[2-napthyl]ethyl)]-N-(methyl)amino]-]-(methyl)homopiperidine     3-[N-(2-[2-napthyl]ethyl)]-N-(methyl)amino]-1-(methyl)pyrrol idine    

      Another preferred sub-class of compounds are those compounds represented by the formula:  
                 
 
 wherein each of R 1  and R 10  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy, cyanoalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R 4  through R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein m is an integer of from 3 to 8; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds are those compounds wherein each of R 1  and R 10  is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl and carboxyalkyl; wherein each of R 2  and R 3  is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkoxycarbonyl, carboxy and cyanoalkyl; wherein each of R 4  through R 11  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof.  
      A more preferred family of such compounds are those compounds wherein each of R 1  and R 10  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl and carboxy lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, hydroxy lower alkyl, halo lower alkyl, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy lower alkyl, phenyl lower alkyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, carboxy lower alkyl, lower alkanoyl, lower alkoxycarbonyl, carboxy and cyano lower alkyl; wherein each of R 4  through R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, naphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof.  
      A more highly preferred family of such compounds are those compounds wherein each of R 1  and R 10  is selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl lower alkyl and lower alkynyl lower alkyl; wherein each of R 2  and R 3  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkenyl, lower alkynyl, lower alkenyl lower alkyl, lower alkynyl lower alkyl, lower alkanoyl and lower alkoxycarbonyl; wherein each of R 4  through R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 4  and R 5  may be taken together to form oxo; wherein R 6  and R 7  may be taken together to form oxo; wherein R 8  and R 9  may be taken together to form oxo; wherein A is selected from phenyl, naphthyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. Compounds of particular interest which fall within the scope of such formula include: 
      2-[N-[2-(3,4-dichlorophenyl)ethyl]-N-(methyl)aminoethyl]-1-(methyl)piperidine     2-[N-[2-(3,4-dichlorophenyl)ethyl]-N-(methyl)aminoethyl]-1-(methyl) homopiperidine     2-[N-[2-(3,4-dichlorophenyl)ethyl]-N-(methyl)aminoethyl]-1 (methyl)pyrrolidine     2-[N-(3-benzothienyl)ethyl]-N-(methyl)aminoethyl]-1-(methyl)piperidine     2-[N-(3-benzothienyl)ethyl]-N-(methyl)aminoethyl]-1-(methyl)homopiperidine     2-[N-(3-benzothienyl)ethyl]-N-(methyl)aminoethyl]-1-(methyl)pyrrolidine     2-[N-(2-[2-napthyl]ethyl)]-N-(methyl)aminoethyl]-1-(methyl)piperidine     2-[N-(2-[2-napthyl]ethyl)]-N-(methyl)aminoethyl]-1-(methyl)homopiperidine     2-[N-(2-[2-napthyl]ethyl)]-N-(methyl)aminoethyl]-1-(methyl)pyrrolidine     2-[N-(3,4-dichlorophenyl)ethyl]-N-(methyl)aminoethyl]-1-(ethyl)piperidine     2-[N-(3,4-dichlorophenyl)ethyl]-N-(methyl)aminoethyl]-1-(ethyl)homopiperidine     2-[N-(3,4-dichlorophenyl)ethyl]-N-(methyl)aminoethyl]-1-(ethyl)pyrrolidine     2-[N-(3-benzothienyl)ethyl]-N-(methyl)aminoethyl]-1-(ethyl)piperidine     2-[N-(3-benzothienyl)ethyl]-N-(methyl)aminoethyl]-1-(ethyl)homopiperidine     2-[N-(3-benzothienyl)ethyl]-N-(methyl)aminoethyl]-1-(ethyl)pyrrolidine     2-[N-(2-[2-naphthyl]ethyl)]-N-(methyl)aminoethyl]-1-(ethyl)piperidine     2-[N-(2-[2-naphthyl]ethyl)]-N-(methyl)aminoethyl]-1-(ethyl)homopiperidine     2-[N-(2-[2-naphthyl]ethyl)]-N-(methyl)aminoethyl]-1-(ethyl)pyrrolidine     2-[N-(3,4-dichlorophenylethyl)aminomethyl]-1-(ethyl)pyrrolidine     2-[N-(3,4-dichlorophenylethyl)aminomethyl]-1-(ethyl)piperidine     2-[N-(3,4-dichlorophenylethyl)aminomethyl]-1-(ethyl)homopiperidine     2-[N-(3-benxothienyl)ethyl)aminomethyl]-1-(ethyl)pyrrolidine     2-[N-(3-benxothienyl)ethyl)aminomethyl]-1-(ethyl)piperidine     2-[N-(3-benxothienyl)ethyl)aminomethyl]-1-(ethyl)homopiperidine     2-[N-(2-[2-naphthyl]ethyl)aminomethyl]-1-(ethyl)pyrrolidine     2-[N-(2-[2-naphthyl]ethyl)aminomethyl]-1-(ethyl)piperidine     2-[N-(2-[2-naphthyl]ethyl)aminomethyl]-1-(ethyl)homopiperidine    

      Additional examples of sigma-2 agonists include compounds of the formula:  
                 
 
 wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 8  and R 9  may be taken together to form oxo; wherein R 10  and R 11  may be taken together to form oxo; wherein each of m, n and p is an integer of from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl, aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R 15  through R 18  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds consists of those compounds wherein each of R 1 , R 4 , R 5 R 6  and R 7  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R 2  and R 3  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each in, n and p is an integer of from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl, aralkanoyl and aroyl; wherein each of R 15  through R 18  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of those compounds wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl; hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanyl, lower alkenyl, lower alkynyl; wherein R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, phenyl lower alkoxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of n and m is a number selected from one through four; wherein each of m, n and p is an integer from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl, phenyl lower alkyl, heteroaryl, lower alkanoyl, phenylalkanoyl, benzoyl, amino lower alkyl, mono lower alkyl-amino lower alkyl and di lower alkylamino-lower alkyl; wherein each of R 15  through R 18  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, pheny lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, halo, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl and lower alkanoyl; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, naphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A more highly preferred family of such compounds consists of those compounds wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl, and lower alkynyl; wherein R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy, phenoxy, benzyloxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein each of m, n and p is an integer from one to four; wherein Z is selected from  
                 
 
 wherein R 14  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl and benzyl; wherein each of R 15  through R 18  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, hydroxy lower alkyl and halo; wherein A is selected from phenyl, naphthyl, benzo[b]thienyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A family of compounds of particular interest are compounds embraced by the formula:  
                 
 
 wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, benzyl and halo lower alkyl; wherein R 2 , R 3  and R 8  through R 11  is independently selected from hydrido, hydroxy, lower alkyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein n is an integer of from four to six; wherein m is an integer of from two to four; wherein A is selected from phenyl, naphthyl, benzothienyl, benzofuranyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, lower alkoxy, halo, halo lower alkyl, amino, mono lower alkylamino and di lower alkylamino; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of compounds wherein each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, methyl, ethyl, propyl, benzyl, and halo lower alkyl, wherein R 2 , R 3  and R 8  through R 13  is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein m is a number selected from four or five; wherein m is an integer of from two or three; wherein A is phenyl or naphthyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamino; or a pharmaceutically acceptable salt thereof. Of particular interest are the following specific compounds: 
      3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine     3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine     3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)homopiperidine     3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)homopiperidine     3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)pyrrolidine     3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)pyrrolidine     3-(1-homopiperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine     3-(1-homopiperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)homopiperidine     3-(1-homopiperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)pyrrol idine     3-(1-homopiperidinyl)-N-(2-[3-benzothienyl]ethyl)piperidine     3-(1-homopiperidinyl)-N-(2-[3-benzothienyl]ethyl)homopiperidine     3-(1-homopiperidinyl)-N-(2-[3-benzothienyl]ethyl)pyrrolidine     3-(1-homopiperidinyl)-N-(2-[2-naphthyl]ethyl)piperidine     3-(1-homopiperidinyl)-N-(2-[1-naphthyl]ethyl)homopiperidine     3-(1-homopiperidinyl)-N-(2-[3-naphthyl]ethyl)pyrrolidine     3-(1-piperidinyl)-N-(2-[3-benzothienyl]ethyl)piperidine     3-(1-pyrrolidinyl)-N-(2-[3-benzothienyl]ethyl)piperidine     3-(1-piperidinyl)-N-(2-[3-benzothienyl]ethyl)pyrrolidine     3-(1-pyrrolidinyl)-N-(2-[3-benzothienyl]ethyl)pyrrolidine     3-(1-piperidinyl)-N-(2-[3-benzothienyl]ethyl)homopiperidine     3-(1-pyrrolidinyl)-N-(2-[3-benzothienyl]ethyl)homopiperidine    

      Additional examples of sigma-2 agonists include compounds having the formula:  
                 
 
 wherein each of R, R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3  and R 10  through R 15  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 8  and R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R and R 1  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 2  and R 3  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 12  and R 13  may be taken together to form oxo; wherein R 14  and R 15  may be taken together to form oxo; wherein each of m and n is an integer of from one to four; wherein Z is selected from  
                 
 
 wherein R 16  is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl, aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl and dialkylaminoalkyl; wherein each of R 17  and R 18  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein each of R 19  and R 20  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof. 
 
      A preferred family of such compounds consists of those compounds wherein each of R, R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3  and R 10  through R 15  is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 8  and R 9  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R and R 1  my be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 2  and R 3  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form oxo or to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 12  and R 13  may be taken together to form oxo; wherein R 14  and R 15  may be taken together to form oxo; wherein each of m and n is an integer from one to four; wherein Z is selected from  
                 
 
 wherein R 16  may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl, aralkanoyl and aroyl; wherein each of R 17  through R 20  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of those compounds wherein each of R, R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl; hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanyl, lower alkenyl, lower alkynyl; wherein R 2 , R 3  and R 10  through R 15  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, phenyl lower alkoxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein each of R 8  and R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 12  and R 13  may be taken together to form oxo; wherein R 14  and R 15  may be taken together to form oxo; wherein m is an integer from 2-4 and n and p are integers of from one to four; wherein Z is selected from  
                 
 
 wherein R 16  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl, phenyl lower alkyl, heteroaryl, lower alkanoyl, phenylalkanoyl, benzoyl, amino lower alkyl, mono lower alkyl-amino lower alkyl and di lower alkylamino-lower alkyl; wherein each of R 17  and R 18  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, pheny lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, halo, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl and lower alkanoyl; wherein each of R 19  and R 20  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, halo, cyano, carboxy, carboxy lower alkyl and lower alkanoyl; wherein A is selected from phenyl, naphthyl, heteroaryl, phenoxy, naphthyloxy, heteroaryloxy, phenyl lower alkoxy, naphthyl lower alkoxy, heteroaryl lower alkoxy, phenylamino, naphthylamino, heteroarylamino, phenyl lower alkylamino, naphthyl lower alkylamino, heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio, phenyl lower alkylthio and heteroaryl lower alkylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy, phenoxy, pheny lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, cyano, amino, mono lower alkylamino, di lower alkylamino, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A more highly preferred family of such compounds consists of those-compounds wherein each of R, R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl, and lower alkynyl; wherein R 2 , R 3  and R 10  through R 15  is independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy, phenoxy, benzyloxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein each of R 8  and R 9  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, phenyl lower alkyl, phenyl, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, carboxy, carboxy lower alkyl, lower alkanoyl, lower alkenyl and lower alkynyl; wherein R 2  and R 3  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 4  and R 5  may be taken together to form a saturated or partially unsaturated carbocyclic group having three to eight ring carbons; wherein R 12  and R 13  may be taken together to form oxo; wherein each of m and n is an integer of from one to four; wherein Z is selected from  
                 
 
 wherein R 16  may be selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl and benzyl; wherein each of R 17  through R 20  is independently selected from hydrido, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, lower alkoxy lower alkyl, hydroxy lower alkyl and halo; wherein A is selected from phenyl, naphthyl, benzo[b]thienyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino, phenylthio, benzylthio and naphthylthio; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, lower alkoxy, lower alkoxy lower alkyl, halo, halo lower alkyl, hydroxy lower alkyl, amino, mono lower alkylamino, di lower alkylamino, lower alkanoyl, lower alkenyl and lower alkynyl; or a pharmaceutically acceptable salt thereof. 
 
      A family of such compounds of particular interest are compounds embraced by the formula:  
                 
 
 wherein each of R, R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, lower alkyl, benzyl and halo lower alkyl; wherein each of R 2 , R 3  and R 10  through R 13  is independently selected from hydrido, hydroxy, lower alkyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein each of R 8  and R 9  is independently selected from hydrido, lower alkyl, benzyl and halo lower alkyl; wherein m is an integer of from two to four; wherein A is selected from phenyl, naphthyl, benzothienyl, benzofuranyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, lower alkyl, lower alkoxy, halo, halo lower alkyl, amino, mono lower alkylamino and di lower alkylamino; or a pharmaceutically acceptable salt thereof. 
 
      A more preferred family of such compounds consists of compounds wherein each of R, R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from hydrido, methyl, ethyl, propyl, benzyl, and halo lower alkyl, wherein each of R 2 , R 3  and R 10  through R 13  is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and halo lower alkyl; wherein each of R 8  and R 9  is independently selected from hydrido, methyl, ethyl, propyl, benzyl and halo lower alkyl; wherein m is an integer of from two or three; wherein A is phenyl or naphthyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamino; or a pharmaceutically acceptable salt thereof. Of particular interest are the following specific compounds: 
      4-[2-(3,4-dichlorophenyl)ethyl]1,4-diazabicyclo[2.2.3]nonane;     4-[2-(3-benzothienyl)ethyl]-1,4-diazabicyclo[2.2.3]nonane;     4-[2-naphthylethyl]-1,4-diazabicyclo[2.2.3]nonane;     4-[2-(3,4-dichlorophenyl)ethyl-1,4-diazabicyclo[3.2.3]decane;     4-[2-(3-benzothienyl)ethyl]-1,4-diazabicyclo[4.2.3]undecane;     4-[2-naphthylethyl]-1,4-diazabicyclo[5.2.3]dodecane;    

      Additional examples of sigma-2 agonists include 5-substituted morphan-7-ones, 5,8-disubstituted morphan-7-ones, iboga alkaloids such as 12-methoxyibogamine (ibogaine) and 13-methoxyibogamine and the like (Bowen, W. D. et al. (1995) “I BOGAINE  A ND  I TS  C ONGENERS  A RE  S IGMA -2 R ECEPTOR -S ELECTIVE  L IGANDS  W ITH  M ODERATE  A FFINITY ,” Eur. J. Parmacol. 279:RI-R3, Bowen, W. D. (2001) “S IGMA  R ECEPTORS  A ND  I BOGA  A LKALOIDS ,” Alkaloids Chem. Biol. 56:173-91), pentazocine (racemic pentzocine, Talwin) and haloperidol. Preferred sigma-2 selective ligands include, but are not limited to, (+)-5,8-disubstituted morphan-7-ones and iboga alkaloids. Preferred (+)-5,8-disubstituted morphan-7-ones are CB-64D and CB-184. CB-184 is a particularly preferred sigma-2 agonist. CB-184 is (+)-1R,5R -E- 8-(3,4-dichlorobenzylidene)-5-(3-hydroxyphenyl)-2-methylmorphan-7-one.  
      The 5,8-disubstituted morphan-7-ones are illustrated by the following general formula:  
                 
 
 wherein: 
      n=0 or 1;     R 1 =lower-alkyl, lower-alkenyl, cycloalkyl, lower-alkynyl, lower-alkylaryl, or hydrogen;     R 2 =lower-alkyl, lower-alkoxy, lower-alkylamino, hydroxy, amino, nitro, halo, azido, or hydrogen     R 3 =aryl, alkylaryl, lower-alkyl, cycloalkyl, lower-alkenyl, lower-alkynyl, lower-alkylaryl, lower-alkoxy, lower-alkylamino, hydrogen, or hydroxy.    

      The term “hydrido” denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or as another example, two hydrido groups may be attached to a carbon atom to form a divalent —CH 2 — group, that is, a “methylene” group; or as another example, one hydrido group may be attached to a carbon atom to form a trivalent —CH&lt; group. Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about ten carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about five carbon atoms. The term “cycloalkyl” embraces cyclic radicals having three to about six carbon atoms, such as cyclopropyl and cyclobutyl. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferable selected from bromo, chloro and fluoro. Specifically embraced by the term “haloalkyl” are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two bromo atoms, such as a dibromomethyl group, or two chloro atoms, such as a dichloromethyl group, or one bromo atom and one chloro atom, such as a bromochloromethyl group. An example of a polyhaloalkyl is a trifluoromethyl group. The terms “alkylol” and “hydroxyalkyl” embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term “alkenyl” embraces linear or branched radicals having two to about twenty carbon atoms, preferable two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The terms “cycloalkenyl” and “cycloalkynyl” embrace cyclic radicals having three to about ten ring carbon atoms including, respectively, one or more double or triple bonds involving adjacent ring carbons. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The “alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term “heteroaryl” embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. The term “alkylene chain” describes a chain of two to six methylene (—CH 2 —) groups which may form a cyclic structure with or without a hetero atom in the cyclic structure.  
      Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.  
      The tem “lower-alkyl” as used herein means linear or branched hydrocarbon chains having from one to about ten carbon atoms and thus includes methyl, ethyl, propyl, isopropyl, n-butyl, see-butyl, and the like.  
      The term “lower-alkenyl” means branched or unbranched unsaturated hydrocarbon radicals of from two to about ten carbon atoms and thus includes 1-ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, isopropenyl, 2-butenyl, isobutenyl, and the like.  
      The term “cycloalkyl” means bridged or unbridged hydrocarbon ring systems having from three to about ten carbon atoms and thus includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, norbornyl, adamantyl, and the like.  
      The term “lower-alkynyl” as used herein means branched or unbranched unsaturated hydrocarbon radicals of from two to about ten carbon atoms and thus includes 1-ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl, and the like.  
      The term “alkaryl” as used herein means a substituted or non-substituted aryl wherein the substitution can be hydrogen or one to about 10 carbon atoms.  
      The term “lower-alkoxy” as used herein means linear or branched alkyloxy substituents having from one to about ten carbon atoms and thus includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and the like.  
      The term “lower-alkylamino” as used herein means linear or branched alkylamino substituents having from one to about ten carbon atoms and thus includes methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, and the like.  
      The terms “halogen,” “halide,” or “halo” as used herein mean bromine, chlorine, iodine or fluorine.  
      The term “aryl” as used herein means optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted imidizoyl, optionally substituted pyridyl, optionally substituted thienyl, indolyl, optionally substituted quinolyl, and the like.  
      The sigma-2 agonists of the invention may also be those analogues of phenylalkylpiperidine compounds (or analogues of the salts thereof) that decrease cellular production of sphingomyelin when provided to recipient cells, and inhibit HIV replication. Phenylalkylpiperidine compounds have the structure:  
                 
 
 where n is 1 or 2, and R is hydrogen, 3-methyl or 4-methyl; or  
                 
 
 where n is 1 or 2; or  
                 
 
 where n is 1 or 2. 
 
      Phenylpiperidine ligands of the sigma-2 receptor have been described in the scientific literature (Maeda, D. Y. et al. (2002) “N-A RYLALKYLPIPERIDINES  A S  H IGH - AFFINITY  S IGMA -1 A ND  S IGMA -2 R ECEPTOR  L IGANDS : P HENYLPROPYLAMINES  A S  P OTENTIAL  L EADS  F OR  S ELECTIVE  S IGMA -2 A GENTS ,” Bioorg. Med. Chem. Lett. February 11; 12(3):497-500). Some of these compounds have shown agonist activity, while others in this class have shown antagonist activity or may be partial agonists. Agonists can be distinguished from antagonists by those skilled in the art.  
      It will be appreciated that the sigma-2 agonists of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in a number of stereoisomeric forms, i.e. enantiomers and diastereomers. Unless otherwise specified herein, the invention is intended to extend to each of these stereoisomeric forms and to mixtures thereof, including the racemates. In some cases there may be advantages, i.e. greater potency, to using a particular enantiomer when compared to the other enantiomer or the racemate in the methods of the instant invention and such advantages can be readily determined by those skilled in the art. The separate enantiomers may be synthesized from chiral starting materials or the racemates maybe resolved by conventional procedures which are well known in the art of chemistry such as chiral chromatography, fractional crystallization of diastereomeric salts and the like. Likewise, the diastereomers can be separated by conventional procedures which are well known in the art of chemistry such as chromatography, fractional crystallization and the like.  
      The synthesis of the morphanones is known to those of skill in the art. For example, several groups (Bertha, C. M. et al. (1994) “A M ARKED  C HANGE  O F  R ECEPTOR  A FFINITY  O F  T HE  2-M ETHYL  (3-H YDROXYPHENYL ) M ORPHANS  U PON  A TTACHMENT  O F  A N  (E) B ENZYLIDENE  M OIETY : S YNTHESIS  A ND  E VALUATION  O F  A N EW  C LASS  O F  E L  R ECEPTOR  L IGANDS ,” J. Med. Chem. 37:3163-70; Bertha, C. M. et al. (1995) “(E)-8-B ENZYLIDENE  D ERIVATIVES  O F  2-M ETHYL  (3-H YDROXYPHENYL ) M ORPHANS : H IGHLY  S ELECTIVE  L IGANDS  F OR  T HE σ   2  R ECEPTOR  S UBTYPE ,” J. Med. Chem. 38:4776-85; Bowen, W. D. et al. (1995) “CB-64D and CB-184: L IGANDS  W ITH  H IGH  S IGMA -2 R ECEPTOR  A FFINITY  A ND  S UBTYPE  S ELECTIVITY ,” Eur. J. Parmacol. 278:257-260) describe the preparation of a number of morphanones within this class of compounds as well as the structure activity relationships of these compounds. Dextro-isomers of the morphanones have a high degree of selectivity for the sigma-2 receptor subtype.  
      When designing and synthesizing a sigma-2 agonist for use according to the present invention, a consideration of the lipophilicity and basicity of the sigma-2 agonist should be made, most preferably so as to permit the sigma-2 agonist to cross the cell membrane and interact with sigma-2 receptors located in sub-cellular organelles (Bowen, W. D. et al. (1999) “S IGMA -2 R ECEPTORS  T HAT  M ODULATE  C ALCIUM  A ND  I NDUCE  C YTOTOXICITY  A RE  L OCALIZED  I NTRACELLULARLY ,” Soc. Neurosci. Abstr. 25:1708, #680.19). Therefore, sigma-2 agonists that are more lipophilic and have fewer sites available for protonation are preferred for use according to this invention.  
      The present invention additionally provides a method of treating immunodeficiency virus infection which comprises administering an effective amount of a sigma-2 agonist, and more preferably a sigma-2 selective agonist to a mammal either infected with such virus or at risk of such infection. Thus, the invention provides a treatment for: humans either infected with HIV or at risk of such infection; felines either infected with feline immunodeficiency virus or at risk of such infection; and simians either infected with simian immunodeficiency virus or at risk of such infection.  
      The effective amount of the sigma-2 agonist to be administered to the mammal, such as a human, is a subtoxic amount. Preferably, the subtoxic amount is an amount that produces little or no killing of uninfected cells. More preferably, the subtoxic amount is an amount that produces little or no effect on the morphology of uninfected cells. The sigma-2 agonist can be administered in a single dose or in multiple doses in a given period of time (e.g., a single daily dose or two or more doses a day). The subtoxic dose depends on the age, weight, general health, and extent of infection being treated. The sigma-2 agonists of the present invention may be administered alone, or in combination with other immunodeficiency virus treatment regimens.  
      A composition is said to be “pharmacologically acceptable” if its administration can be tolerated by a recipient patient. An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient. The administration of such compounds may be for either a “prophylactic” or “therapeutic” purpose. The compositions of the present invention are said to be administered in a “therapeutically effective amount” if the amount administered is physiologically significant to provide a therapy for an actual infection. When provided therapeutically, the compound is preferably provided at (or shortly after) the onset of a symptom of actual infection. The therapeutic administration of the compound serves to attenuate any actual infection. The compositions of the present invention are said to be administered in a “prophylactically effective amount” if the amount administered is physiologically significant to provide a therapy for an potential infection. When provided prophylactically, the compound is preferably provided in advance of any immunodeficiency virus infection or symptom thereof. The prophylactic administration of the compound serves to prevent or attenuate any subsequent infection.  
      The compounds of the present invention can be administered in conventional solid or liquid pharmaceutical administration forms, for example, as uncoated or (film-) coated tablets, capsules, powders, granules, suppositories or solutions. The active substances can, for this purpose, be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases. The therapeutic compositions obtained in this way typically contain from about 0.1% to about 90% by weight of the active substance.  
      Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified.  
     EXAMPLE 1  
     Sigma-2 Receptor Agonists Inhibit HIV Infection of Lymphocytes by Reducing Membrane Sphingomyelin Content  
      HIV infection of CD4 +  lymphocytes and release of virions occurs in lipid rafts; cholesterol- and sphingolipid-rich microdomains of the plasma membrane. Reducing membrane cholesterol content disrupts lipid rafts, and therefore has been found to also reduce HIV infectivity of lymphocytes and to diminish virulence of the virions released (Nguyen, D. H. et al. (2000) “E VIDENCE  F OR  B UDDING  O F  H UMAN  I MMUNODEFIENCY  V IRUS  T YPE -1 S ELECTIVELY  F ROM  G LYCOLIPID -E NRICHED  M EMBRANE  L IPID  R AFTS ,” J. Virol. 74:3264-3272; Liao, Z. et al. (2001) “L IPID  R AFTS  A ND  HIV P ATHOGENESIS : H OST  M EMBRANE  C HOLESTEROL  I S  R EQUIRED  F OR  I NFECTION  B Y  HIV T YPE  I,” AIDS Res. Hum. Retrovir. 17:1009-1019). Reducing membrane sphingomyelin also disrupts lipid rafts, and therefore would produce similar effects. Sigma-2 receptors are enigmatic receptors expressed in various tissues that recognize diverse psychoactive compounds. It has been found that sigma-2 receptor-activation reduces levels of membrane sphingomyelin in breast tumor cells (Crawford, K. W. et al. (2002) “S IGMA -2 R ECEPTORS  R EGULATE  C HANGES  I N  S PHINGOLIPID  L EVELS  I N  B REAST  T UMOR  C ELLS ,” Eur. J. Pharmacol 443:207-209). Additionally, sigma-2 receptors were found to be localized to lipid rafts (Gebreselassie, D. et al. (2002) “Sigma-2 receptors are localized to sphingolipid/cholesterol-rich membrane rafts,” Proc. Amer. Assoc. Cancer Res. 43:725, #3597). In addition, sigma-2 receptor activation may inhibit P-1-3′ kinase signaling, an effect that should inhibit HIV infection of lymphocytes and macrophages (Francois, F. et al. (2002) “A R OLE  F OR  P13-K INASE  S IGNALING  D URING  HIV I NFECTION  O F  P RIMARY CD 4+ T L YMPHOCYTES  A ND  M ACROPHAGES,”  9th Conference on Retroviruses and Opportunistic Infections, #171, 2002; http://www.retroconference.org/2002/Abstract/12694.htm).  
      Methods: Membrane sphingomyelin is metabolically labeled in H9 lymphocytes by incubating the cells with [ 3 H] palmitic acid in supplemented RPMI media for 48 h. Labeled media is removed and cells are incubated in the presence or absence of various concentrations of the sigma-2 receptor agonists CB-184 or haldol (haloperidol) for 24 hours. Total lipids are extracted and the dried organic layer is chromatographed on Silica G-60 plates. Sphingomyelin spots are scraped and quantified by liquid scintillation counting.  
      CEMX174 cells transfected with a luciferase gene driven by the Simian Immunodeficiency Virus (SIV) LTR are used in infectivity assays. Cells are then treated with sigma-2 receptor agonists at various concentrations followed by incubation in the presence or absence (control) of HIV. Luciferase activity quantifies HIV replication.  
      Results: Treatment of H9 cells with the sigma-2 receptor agonist CB-184 produced reductions of about 39% and 45% of control levels of membrane sphingomyelin at doses of 0.3 μM and 1 μM, respectively ( FIG. 1 ). Similar results are obtained with haldol ( FIG. 1 ). Haldol (haloperidol: Ortho McNeil Pharmaceutical Inc.) is a butyrophenone used in the treatment of Schizophrenia and other psychiatric conditions (Warraich P. S. et al. (2002) “H ALOPERIDOL  F OR  T HE  A CUTE  P HASE  O F  S CHIZOPHRENIA ” Cochrane database system Rev. (3):CD001951; Lonergan, E. et al. (2002) “H ALOPERIDOL  F OR  A GITATION  I N  D EMENTIA ,” Cochrane Database Syst. Rev (2)CD002852). Haloperidol has been shown to be a sigma-2 agonist (Vilner B. J. et al. (2000) “M ODULATION  O F  C ELLULAR  C ALCIUM  B Y  S IGMA -2 R ECEPTORS : R ELEASE  F ROM  I NTRACELLULAR  S TORES  I N  H UMAN  SK-N-SH N EUROBLASTOMA  C ELLS ,” J. Pharmacol. Exp. Ther. 292 (3): 900-11).  
      Structurally-diverse sigma-2 receptor agonists (CB-184, CB-64D, BD737, and haldol) produce dose-dependent inhibition of HIV infection ( FIG. 2 ). This inhibition of HIV infection occurs at doses within the range of concentrations of CB-184 and haldol that produce reductions in membrane sphingomyelin, as shown above in  FIG. 1 . In these experiments, lymphocytes transfected with a luciferease gene driven by the Simian Immunodeficiency virus (SIV)LTR were incubated for 24 hours in the presence of the indicated dose of sigma-2 receptor agonist. The drugs were then removed, cells were washed and exposed to HIV for 24 hours. Cells were then lysed and luciferase activity quantified. Luciferase activity indicates the level of infectivity of the HIV virions. All of the compounds evaluated with sigma-2 agonist activity inhibited HIV infection at concentrations that were non-toxic to lymphocytes.  
      The sigma-2 receptor antagonist N-phenethylpiperidine (AC-927) reversed the ability of the potent sigma-2 agonist, CB-184, to inhibit HIV infection of lymphocytes. Different doses of the antagonist AC-927 abrogate the inhibitory actions of CB-184 at various doses and also with exposure to different HIV viral titres ( FIG. 3 ,  FIG. 4 ,  FIG. 5 ). The ability of the antagonist to inhibit the effects of the sigma-2 receptor agonist provides strong evidence that the inhibition of infection is indeed mediated via the sigma-2 receptor.  
     CONCLUSIONS  
      The results presented here indicate that structurally-diverse sigma-2 receptor agonists, at non-toxic concentrations, prevent HIV infection of lymphocytes. Such inhibition may be produced through the reduction of lymphocyte membrane sphingomyelin. This inhibitory action of sigma-2 receptor agonists can be reversed by selective receptor antagonists. Collectively, these findings support a role of sigma-2 receptors in HIV infection and support the use of sigma-2 agonists therapeutically in the treatment of HIV infection. This host-targeted intervention may circumvent the problems related to viral drug resistance providing which can have exceptional utility in treating HIV infection.  
      All publications and patents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.  
      While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.