[PAGE 1]
Request for renewol of No 113-149

t. Backcround Informatlon

Since July 195l a project, dealgned to develep a synthctle drug shich would be as safe as codelne froa the polnts of view of toxlcology, antitussive activity and addiction llabtlity as Is codeine, has been carried cn wlthin the National lastltute of Miental Heolth Addiction Research Center, Publle Health Service Hospital, Lexingfon, Renlucky. This project hes been financed -ln lerge part by funds fren the Offlce of Naval Research.

A syathstle substltute for codeine is badly needed sInse aplum, er morphiae derivzd from oplum, conatltutes the only source oi codelne. This meens.that, unless a synihetlc is developed, tha United States must continve to stockpile oplum egoinst Phe possiblllty of opium supoiies being cut off duriag wur. The impertance of the project ln relsfionshi: to the netlonel defesse Is thereiore cbvious; but, vafortunitnly the fecllitles of the bild: Addiaticn Fessarch Gaater dts ot sufflclent to cerry out the work unless addltionsl fun's ars zviolied by the Cezsrtment oi Defenss.

A-314

83-

PROJECT DESCRIPTION

THE ADDICTION LIABILITY CF SYNTHETIC SUESTITUTES FOR CCDEINE.

[PAGE 2]
11. Wort Accomplished to Date

This is summarized in the Annual ?rogress Repert sent to Dr. F. H. Culmby, Head of ths Physlology Branch, Office of Navat Research,ia Janudry 1954,

The most promising drug yet developed ln the progran Is the dextrorototory 3emethylether of N-methylmorphinan. Thls compound is completely devcid of addiction liablllty: and is of sufficlently los toxiclty to be safc for human use. la experlmental aaimals i has considereble antitussive actlvity end trlal for antitusslve actlvlky under ctbabcal conditions Is now underway. The resuits obielned with thls drug os a ellnicel antitussive are still conflicfing and it is not yet certoin whether lt pouid be en edequate substitute for codelne for this purpose. it ls also knewn that the drug 1s complateiy ineffective as an anaigeslc and would not serva as a substitute for codelns for this purpose.

Di, d, and 1 2-2-diphenytaminecthyl valerates have been shorn fo paiszss addiction liadilliy slmilar to that of codelne. Pralininary cllalcal trfals with these drugs hays becs recoomenced,

Ot-2-2-dtphenyt-4-dtocthyle=lnz hutyrats las prc..rtlas simllar to those of the valerates deseribed in the precedlng paragraph and, iherefore, mey serve ss a sulsfltute for codeine.

A-313

[PAGE 3]
11. Fork Accesolished ta Date

This Is summarized in thz Arnual 'rogress Report sent to Dr. F. H. Culmby, Head-of the Physlolocy Branch, Office of Neval Rescarch, ia january 1954.

The most promisins drug vat developed In the progrem Is the dextrorotatory 3-methylether of N-pethylnorphinan. This compound ls somplctely devoid of addictlon liobllity and Is of sufficlently lou toxiclty to be sofe for human use. In experimental anlmsls It hes consldcrable antitussive actiylly and trlal for entitussive actlyity under clinical conditlons Is now underway. The results cbtelned ith this drug es e clinlcel antitusslve ere still conflictias and It Is not yct certaln whether it xould be an edequate substltute for codzinc for this purpose. It.ls olso knoen that the drug ls completeiy Inefiective as an analgesic and wnuld not serve as a substltute for codeins for this purpose.

D1, d. and 12-2-dlphenylamiacethyl valerates have teen shoun to posseas addletion liabillty simiier to that ef codeine. Preliminsry cliaical. trlals with thase drugs have been.recotnen-ied.

Ol-2-2-dlahaayt-4-diactbytestno tutyrala has pcopsriies zloller to those of the valeretes described in the preseiing paragraph end, therefere, may serve es e substltute ior ccdeida.

4-312

[PAGE 4]
D-2,N-dlmethyl-hydroxy-norphInan is completely Inert In man and devold of addlction Ilabillty. The levorotatory form of this drug has alld morphine-llke effects and partially suporesses abstlnence from morphine. Its addictlon lisbiilty Is probably somewhat greater than that of codelne and, on the other hand, Is far less than that of morphine. Depending.on the ouicome of cliaical trlols with the d-methytether of Oromoran, the compound. might be constdered as a potentlal. substitute for codelne. It has one advantage over d-methyl Dromoran In that 4 It wilt probably bea mild analçeslc drug similar to codeine. Bork glth these compounds Is still continuinge

4-4-diphsnyl-é-dimethylamino-hexenone-3, & member of tha methodone group, wlll appareetiy have addlction llabillty of a low order. Thls compound is in use In Germany as an 'antitussive and further vork with it Is ImosratIve. Ill.Need for Cntiavation nf the Proiact

Although seven compounds that have potentialltles as codetne substituies have bren vncovered by lhe procram, only one of these so far Is In clinlcal trlal. end it ls. unknowa whether they will prove satisiactory in clinlcal vae. The more comppunds develoved, the greater will be the chances of findlng en adequate codeiae substltute.

A-311

[PAGE 5]
IV.Cork Proonsed

Durlng the perlod July 1954 to July 1955 we hopz to complete the work on the Isomers of 2,N-dlmethyImorphinan and on 4-4-dlphenyl-0-dimethytamino-hexanone-3. In addition to this, we hope to examine the potentlalitles of the syristyt ester of morphine end of 3-hydroxy-N-msthylmorphinen.

Two new approaches to the problem will be sxplored. One oi thesg conslsts. of attempts to attenuate the potency -and addiction llabillty of the syathetic drugs methadone and Dromoran by alxing them with apeclfic sntagonists, ti-eliylnormorphine end N-aliyinordromoran, and such other anfagauists es may be recommended by the Drug Addictlon Camalttee of the Natlonal Reseerch Councll. In this coanection it may be necessary to study the properties of a nunber of new aatacoaists In the hope of findiag antsgonists which are oraily effectlve. The folloalng antagoaists wlll be examined: (lt N-otlylzordlacetyimorphlne, 12} N-propyi-dihydronormorphine, [31 dextroand levorototoryellylnordromoran, 14) levorotatory-3-methyiather af N-allylnordronoren, I5) Ieveretetory-Nepropsrsy'- nordromoran, and 1cl levorotatory-3-asetoxy-N-allyinordromoron.

of exizndlng the supzly of soceine by conbining lt with a nerual:: Slocking agent, beta-dicthylaminosthgipropyl ecetate, which àos

A-310

[PAGE 6]
been reported to inerease the potency and length of astlon of anslgesic druçs In anlmals.

v. Methods

The methods to be used ore the standard addlctlon llablilty testIng methods of the Niliit Addictlon Resedrch Center. These have been described in detall ln previous project deserlptions and In prevlous Annual Reports. For detalls thase should be consulted.

VI. Evaluatlon of Deta

The evaluatlon of data has also beer dlscussed in prevlous descriptions which should be consulted.

VIi.Location of irolect

The work will be carrled out et the NtiH Addietion Research Center, rubile Hizalth Service tosoitol, Lexinpton. Kentucky. This Institution provldes the two gecessary fasllitles for the tvpe of vork to be vnderiaken: (i) a pool of patients who wlli volunteer for tha expzrlments with drugs, and 12) strict eevironmentai control which preventt the Introduction of drugs ather than those under study, Into the exoerimental sltuation,

[PAGE 7]
Vill. Exoerlmental Personnel

The sork =lll be carrled out under the direction of Harrls Isbell, M.D., Director of Research, NiMH Addiction Reteerch Center. This investlgator has had ten years of exoerience In research in norcotic drug addiction ond has published meny papers In the fleld. He wlli be assisted by two other expertenced physicians, Dr. H. F. Freser and Dr. Abroham Eikler, both of whom heve had extenslve experience In research tn eddictlon.  In addition to these medical personnel, the parttime services of a Blochemist and Research Psychologist wlll be made avallable. A speclal ward for conducting the studles Is currently in operatlon.

IX. Estimated Cost

l.Personnel

ó Psychlatrle Aide, GS-5
1 Physical Science Alde, GS-4
1 Physlologlst, GS-7

2. Reserve for night, holldey and overtime pay

3.Miscellaneous expenses Total

1 Item 3, mlscellaneous expenses, includes money for the purchase of drugs, chemicais, glosswere, eleetroencephalcgraphic and photographic paper, needles, syringes, ete.

t. i Parrls Isbell, M.D. Dipector of Rescorch

A-308

Hi:rn