Abstract:
Tetrahydro-N-methyl-2,2-diphenyl-3-furanomethanamine (AE37Met) is a highly selective ligand of the extrasynaptic NMDA receptors, of the M2 muscarinic autoreceptors and of the sigma-1 (σ1) receptors, with prototypical brain, preventive and therapeutical, protective activity. This invention concerns the prototypical profile of AE37Met and its pharmaceutically acceptable salts, with cytoprotective activity, more specifically for brain glial cells and neurons, against the neuro-degenerative diseases (e.g. Alzheimer&#39;s, Huntington&#39;s and Parkinson&#39;s diseases, depression, brain ischemia/hypoxia, traumatic brain injury and epilepsy), by the highly selective antagonisms, exerced by AE37Met, on the extrasynaptic NMDA glutamatergic receptors [eNMDA(−)] and on the M2 muscarinic cholinergic autoreceptors [M2(−)], associated with a highly selective sigma-1 agonism [σ1(+)]. The above prototypical profile was observed only with AE37Met between the other family members (AE14, AE37 and their enantiomers).

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    This application is a Continuation-In-Part under 35 U.S.C. §120 based upon co-pending U.S. patent application Ser. No. 14/395,581 filed on Oct. 20, 2014 and upon co-pending International Application No. PCT/GR2013/000018 filed on Apr. 3, 2013. Additionally, this present application claims the benefit of priority of U.S. patent application Serial No. 14/395,581 filed on Oct. 20, 2014, International Application No. PCT/GR2013/000018 filed on Apr. 3, 2013 and Greek (GR) Application No. 20130100181 filed on Mar. 28, 2013. The entire disclosures of the prior applications are incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
       [0002]    The present invention concerns the prototypical profile of tetrahydro-N-methyl-2,2-diphenyl-3-furanomethanamine (AE37Met) and the new putative brain, preventive and therapeutical, protective properties of AE37Met characterized by highly selective antagonisms of the extrasynaptic NMDA receptors [eNMDA(−)] and of M2 muscarinic cholinergic autoreceptors [M2(−)], associated with a highly selective sigma-1 (vs sigma-2) agonism [σ1(+)]. The present invention relates to a prototypical profile of AE37Met for use in connection with at least preventing and therapeutical protection of the new putative brain. 
       BRIEF SUMMARY OF THE INVENTION 
       [0003]    The present invention provides an improved prototypical profile of AE37Met, and overcomes disadvantages and drawbacks of the prior art. As such, the general purpose of the present invention, which will be described subsequently in greater detail, is to provide a new and improved prototypical profile of AE37Met and method which has all the advantages of the prior art mentioned heretofore and many novel features that result in a prototypical profile of AE37Met which is not anticipated, rendered obvious, suggested, or even implied by the prior art, either alone or in any combination thereof. 
         [0004]    To attain this, the present invention essentially concerns the prototypical profile and the putative brain, preventive and therapeutical, protective properties of tetrahydro-N-methyl-2,2-diphenyl-3-furanomethanamine (AE37Met) and its pharmaceutically acceptable salts, with cytoprotective activity, more specifically for brain glial cells and neurons, against the neurodegenerative diseases, via their highly selective antagonisms of extrasynaptic NMDA receptors [eNMDA(−)] and of M2 muscarinic cholinergic autoreceptors [M2(−)], associated with their highly selective sigma-1 agonism [σ1(+)]. In particular, concerning the Alzheimer&#39;s disease (AD), the prototypical ([eNMDA(−)], [M2)] and [σ1(+)]) neuroprotection of AE37Met allowed the putative valorization of inhibitors of acetylcholinesterases (IAChEases) as therapeutical agents against Alzheimer&#39;s disease (AD). 
         [0005]    There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood and in order that the present contribution to the art may be better appreciated. 
         [0006]    Numerous objects, features and advantages of the present invention will be readily apparent to those of ordinary skill in the art upon a reading of the following detailed description of presently preferred, but nonetheless illustrative, embodiments of the present invention when taken in conjunction with the accompanying drawings. In this respect, before explaining the current embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of descriptions and should not be regarded as limiting. 
         [0007]    As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention. 
         [0008]    It is therefore an object of the present invention to provide a new and improved prototypical profile of AE37Met that has all of the advantages of the prior art and none of the disadvantages. 
         [0009]    It is another object of the present invention to provide a new and improved prototypical profile of AE37Met that may be easily and efficiently manufactured and marketed. 
         [0010]    An even further object of the present invention is to provide a new and improved prototypical profile of AE37Met that has a low cost of manufacture with regard to both materials and labor, and which accordingly is then susceptible of low prices of sale to the consuming public, thereby making such prototypical profile of AE37Met economically available to the buying public. 
         [0011]    Still another object of the present invention is to provide a new prototypical profile of AE37Met that provides in the apparatuses and methods of the prior art some of the advantages thereof, while simultaneously overcoming some of the disadvantages normally associated therewith. 
         [0012]    Lastly, it is an object of the present invention to provide a new and improved method of using a AE37Met for preparing pharmaceuticals including the steps of preparing an effective amount of a compound selected from the group consisting of AE37Met, a pharmaceutically acceptable salt of AE37Met, and combinations thereof, with brain, preventive and therapeutical, protective activity. Using the compound for the preparation of at least one pharmaceutical. Then administering a predetermined amount of the pharmaceutical to an individual. 
         [0013]    These together with other objects of the invention, along with the various features of novelty that characterize the invention, are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and the specific objects attained by its uses, reference should be made to the accompanying drawings and descriptive matter in which there are illustrated embodiments of the invention. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0014]    An embodiment of the present invention concerns the prototypical profile and the new putative therapeutical properties of tetrahydro-N-methyl-2,2-diphenyl-3-furanomethanamine (AE37Met) characterized by affinities, for sigma-1 vs. sigma-2 receptors, with median concentrations of binding (IC50) being 0.67 microMolar (μM), for sigma-1 receptors and IC50&gt;10 μM, for sigma-2 receptors. AE37Met as referred to in the present invention, may include compounds having the general formula A: Tetrahydro-N-methyl-2,2-diphenyl-3-furanomethanamine or Tetrahydro-N-methyl-2,2-diphenyl-3-furanomethanamine hydrochloride. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0015]    The affinity of AE37Met, for the N-methyl-D-aspartate (NMDA) receptors, is low and optimal for a selective activity on the extrasynaptic NMDA receptors, with an IC50=1.0 μM and for sodium channels with IC50=5.7 μM. Finally, the IC50 for M2 and M3 muscarinic receptors were, respectively, 2.77 and 4.35 μM, with significant functional antagonisms from 3.0 μM of AE37Met (guinea pig left atria and ileum, respectively). 
         [0016]    In vitro (Rat hippocampal slices) studies and in vivo experiments (Maximal Electrochoc Seizures (MES) or Pentylenetetrazole (PTZ) convulsions and A1325-35 induced neurodegeneration, in mice, demonstrated the highly selective antagonism of brain extrasynaptic NMDA receptors [eNMDA(−)], by AE37Met. Indeed, in good agreement with its optimal low affinity for the NMDA receptors (IC50=1.0μM), no memory perturbations, coming from a possible synaptic inhibition of NMDA receptors, were observed from 0.1 to 45 mg/kg, per os, (po), of AE37Met, in mice. Moreover, highly selective antagonism of the presynaptic M2 muscarinic autoreceptors of the brain cholinergic neurons (inducing acetylcholine release stimulation) was obtained by AE37Met [M2(−)]. 
         [0017]    Finally AE37Met, by its highly selective sigma-1 agonism [σ1(+)] and the resulting antagonism of the astrocytic nicotinic receptors, prevented (synergistically with its [eNMDA(−)] component) the initiation and the amplification of the neuroexcitotoxic processus and consolidated the Endoplasmic Reticulum (ER)—Mitochondrion system by activating the anti-apoptotic pathways (stimulation of Bc1-2, Bc1-xL proteins) and restored the mitochondrial function of the neurons preventing the oxidative stress and apoptosis (neuronal death). 
         [0018]    The above was clearly demonstrated by the capacity of AE37Met to antagonize the mitochondrial toxicity of pentylenetetrazole (PTZ) by increasing the latency of lethality of PTZ (130 mg/kg, intraperitoneal, ip) in mice, by 3.10 and 18 fold at, respectively, 3.10 and 30 mg/kg of AE37Met (po). These sigma-1 activities of AE37Met were completed, specifically in neurons, by inhibition of their entry in the cell cycle, as this entry is always fatal for neurons. 
         [0019]    In good agreement with the aforementioned protective components, AE37Met, at lower doses 0.3 to 3 mg/kg, intraperitoneal (ip), in mice, antagonized the Aβ25-35 induced amnesia and neurotoxicity and, at higher doses (10 to 30 mg/kg, po) or 5 to 15 mg/kg, (ip), protected against MES/PTZ convulsions or brain ischemia, respectively, in mice. 
         [0020]    It is noteworthy that AE37Met at 1 to 10 μM exhibited the first antagonistic effects against the NMDA (10 μM) induced functional excitotoxicity, in rat hippocampal slices, suggesting that the most important part of the obtained neuroprotection at 0.3 to 3.0 mg/kg, ip, (corresponding at 1 to 10 mg/kg (po) and 1 to 10 μM, in the above test on hippocampal slices), in the Aβ25-35 protocol, in mice, originated from the [eNMDA(−)] component, however, reinforced synergistically by [M2(−)]. The antagonisms [eNMDA(−)] and [M2(−)] prevented the brain oxidative stress and the dysfunction of the brain cholinergic systems, the latter acting synergistically with [eNMDA(−)] for the brain protection, by the regulation of the blood flow in brain microvessels, via the [M2(−)] induced release stimulation of acetylcholine . Indeed, concerning the chronic mild brain stress of the neurodegenerative diseases (e.g. Alzheimer&#39; s, Huntington&#39;s, Parkinson&#39;s, diseases and depression), in the contrary to the symptomatic treatments used currently against the above diseases, AE37Met antagonizes their pathophysiological causes i.e., the endocellular biochemical stress and, concerning the neurons, also their fatal entry in the cell cycle. 
         [0021]    Similarly, concerning the hard neuronal stress pathophysiological states (i.e., the epilepsy and ischemia/hypoxia) experimental protocols, the high protective effects obtained with AE37Met at 10 to 30 mg/kg (po), in mice submitted at MES or PTZ convulsions, as well as the significant antagonism obtained with AE37Met at 5 to 15 mg/kg (ip), in mice submitted at brain ischemia (doses corresponding at 10 to 30 μM, for convulsions protection, and 15 to 45 μM, for brain ischemia antagonism, in the hippocampal slices protocol), clearly suggested that also in the above hard brain neuronal stress pathophysiological states, with high functional NMDA excitotoxicity, the most important part of the AE37Met obtained neuroprotection, originated from the [eNMDA(−)]. 
         [0022]    Indeed, this component of the AE37Met is very important concerning the prevention or the therapeutical protection against the pathophysiological or elderly induced brain stress, in neurodegenerative diseases and more specifically in the Alzheimer&#39;s diseases (AD). Moreover, the [eNMDA(−)] component, is the putative sine qua non condition for an appropriate valorization of the third component [σ1(+)]. Indeed, the [σ1(+)] activated antiapoptotic pathways could be, in the absence of significant [eNMDA(−)], at best, palliative or, most probably, deleterious. In good agreement with the above considerations, AE14 (tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanomethanamine), which exhibited high and selective sigma-1 agonistic activity but not significant (IC50 more than 10 μM) affinity for NMDA receptors and AE37 (tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanomethanamine) with also sub-micromolar and selective sigma-1 agonism but very low (IC50=8.0 μM) affinity for the NMDA receptors, exhibited significant excitoneurotoxic effects (higher for AE 14) in the (in vitro) specific evaluation test of their functional excitotoxicity, on hippocampal slices. On the contrary, no excitotoxic effects were observed with AE37Met. Moreover, no significant neuroprotection was observed with AE14 or AE37 when their putative neuroprotection was evaluated against the NMDA (10 μM) induced functional excitotoxicity in hippocampal slices, whereas AE37Met exhibited a high dose (concentration)-dependant neuroprotection, in good agreement with the aforementioned neuroprotection of AE37Met against the mice brain ischemia, in which AE14, AE37 and their enantiomers were inactive ( worsening was even observed with AE14 and AE37 enantiomers). 
         [0023]    Of particular interest was the brain protection of AE37Met when it was co-administered with inhibitors of the acetylcholinesterases (IAChEases), which are used as symptomatic drugs (principally Rivastigmine, Donepezil and Galantamine) against the AD. The antiamnesic action of AE37Met, in the appropriate experimental protocols (Y-maze, step-through) of neurodegenerative amnesias obtained by intracerebral injection of soluble amyloids A1325-35 in mice is outstanding (higher than the sum of the antiamnesic effects of AE37Met and IAChEases : typical examples Rivastigmine or Donepezil, when administered alone). 
         [0024]    The above neuroprotective activity of AE37Met is completed by the putative prevention of the severe cholinergic adverse effects (nausea, vomiting, diarrhea, bradycardia) of IAChEases via the antagonistic effects of AE37Met (from 1 to 10 mg/kg, ip, in mice) on M2 and M3 muscarinic receptors in the periphery, therefore permitting the use of higher and more efficient doses of IAChEases against AD. 
         [0025]    In vivo experiments with the appropriate protocols, in mice: forced swimming (Porsolt) and open field, with AE37Met, demonstrated the prototypical antidepressive action (high anti-immobility activity from 5 mg/kg, po, in the Porsolt test) which is associated with neuroprotective effects, confirmed by the neuroprotective antagonism of the neurotoxic effects of pentylenetetrazole (PTZ) on the mitochondria of neurons and also by the aforementioned anti-Aβ25-35 activity. The combination of the anti-immobility activity with antiapoptotic and neuroprotetive effects is a new inventive approach of therapeutic (and not only symptomatic) confrontation of depression, as there is mounting evidence that depression is a neurodegenerative disease, via endoneuronal biochemical stress and apoptosis of neurons 
         [0026]    While embodiments of the prototypical profile of AE37Met have been described in detail, it should be apparent that modifications and variations thereto are possible, all of which fall within the true spirit and scope of the invention. With respect to the above description then, it is to be realized that the optimum dimensional relationships for the parts of the invention, to include variations in size, materials, shape, form, function and manner of operation, assembly and use, are deemed readily apparent and obvious to one skilled in the art, and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention. And although preventing and therapeutical protection of the new putative brain has been described, it should be appreciated that the prototypical profile of AE37Met herein described may also be suitable for additional brain treatment or protection. 
         [0027]    Therefore, the foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.