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Roport Propared Ey: Harris Lotell, H.D. 1 lay 1962

For the Toviou: 1 Fay 1061 to 1 fay 1962

M: 301:140

CONTRACT: mónz 21-€1

ADNAL RATE:

CORTRACTOR:

U, S, Publio Health Borvica Hational lnstisuto of Rontal lealth Lothosda 14, Faryland

(Inquirios concornins rinancos should be cont to this adárons.)

PRINOIPAL DNIVESTIGATOR: Harris Istell, H.D.

Assiotants:

F. FnGer, H.D. 2. Vikler, H.D. D. 3. Rosonborg, H.D. C. E.tn 0. D. Vea lor Larbara . Smith E. L. Glass C. S. Ceivora V. K. Velah Irvin Linkler Vivian L. Jornings Faynond Cox

210 (63)

AINIUAL FROGRCES REPCRT

Declassified by FEe-197775.

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TITLS OP PROJECTi Eo Addiction Liabilitieo of Syathotio Surstitutes for Codoine.

Objoctivos: To find a oynthotic analgosic and antitussive drus whioh vould te as safo or sañer than codoino.

A1 STRACP (OR SUELRY) OF RESULES:

a. Since atart of projoet: Soo annual reports for 195a throuch 1960.

B. During ths ourrent roncst poriod: Tostinc has toen completed or is in pro:ross on tho folloving compounds:

1.Dextro-3-dirothylanino-1,1-diphorylbutyl ethyl sulfone Hel (Anc I-C-26). Thio coapound was Found to have addlotivenoss sroator than aodeine and has deon dropred frou furtherconsiceration.

2.Styl-1(2-Carbaeylothr1)-h-phenylniporidipo-hcarboxylotoliel (ang I-D-20). Eis meperidine congener 1s ofreotive orally as an antitusgivo in dssos of 50 nt. Iu induces only a partial spectrum or norphine-like bohavioral sflcota, even in dosos of lo0o a, and wll suppress abstinoneo trom norphine only partially. Its acdictiveness is less than that oº codeina.

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2.1,2-Dinothy1-S-nhonyl-3-ppopionoxy-pyarolidine Hel (AC I-O-l). Tio maperidine congener, which is roported to be an efrootive anelgesie orelly, has less acdiotivonesa than coduine. hhwever tozicity may preyont clinical usage.

4. 2.2-Dipheny1-4(1-14 (U-olporidino)-4-carvexamido) -vAperidine)-butyronttrile (Ano 1-D-21). Mis meroridine conçener is an efleotive analgeslo thąt has boen roported not to be addietivé ia dogo. It is half as potent as morphino in indueins morphino-liko tehavioral ehanges vhen Civen suboutaneously, it suppresses arstinonce eftoctivaly, but follavins substitution (subeutanoouslz) for norphine for l0 dayo, or follosing direct. adaiction for 25 cags, only minor signs os atstinonoa vers detectod. Eiio interestins dissoeiation of effoctá may bo due to low solubility of the compound, vith reoultant slov absorptlon after subeutancous injection and precipitation in tissue.. Evaluation or tho ratorial orally 1sireaploto.

5. 1-2:-8yroa7-2.5.0-trinetby1-6.7 benscaomphon e (ARC Ieh-2). Zis carpound is a potont annlgodic in pan, Ie is as potens as porphine tohaviorally tut, surprisinsly, is rolativoly Inesseative in supprossing atstinence. Howovar ào compound did areata addietion nearly es intanse cs thst produued ly morphine in a short dirost adeloslon enerimant. Studieo af tho conpound are continuing.

B=382

Fago 3

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6.1-lydroxyathozyethyl-4-phonyi-a-mroplory1-
piporidine lel (ARd I-D-22). Tie antitusaive neperidine
conconer is an efreutivo antitusuive. Dpfinita codoine-like
Lonaviorai erloota vere not obaervod with doses of 500 ms:
1700-1l00 ms dafly partially suppressed ntatinonce fres
moiphine. This compoud is loss addletivo than codeine. 7. 1-Dirothviasino-3-phenrlindane Hel (As0 I-N-1).

This cospound is the prototypo or a now sories ol analgzaics that roscable esphetasine more than morphine. Is is analgesie in san, but in our experimonta it did not induca norphino-liko behavioral changs after 20o ms orally, did not guppress abstinence, and did not eroate adaiation.

8. 2-hnino-indana Lol (ASC I-N-2). Thio eonpound 1s a mord potont agent than I-ll-1 (seo above). It did pot eroato ropphino-like bohavioral effcets, did not supress atstinonce and did not areate cddistion.

9.21-droxr-5.9-dinetyt-2-(=,3-dinethylallv1)- 6.7-bensooorphan (Anc II-C-2). Tis corpound is an cpiate antagonist that bas taon reportod to ko hals as erfeutivo as morphino as en analgesie in man. It doos not causo morphinelllo tehavicral offeets and cupprosses atstineneo only Fartially. Dioct adliction axperironts aro ip progross, but pationta are rafusiag to continue on tho drus hocause of laok or attraetiva oul joctivo orroot, nontal conuaion, and iiritatien ot cuteatanlou tissucs at injeotion pitcs. B-381 R-2A1

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10. 1-(0-Chlop-rhenotay1)-2-rethyl-0,7-diaothoxy-1.0,2.4-tetrabydroissquicoline Hal (A20 I-K-1). Tooting or this cubstanoe vas corplotod during tho yeor and rocults confirmod thoso previouoly ceserited. Te compound, thouch an cnalgeale olinionlly, hao loss addiotivenoss than coduino 2 and oveu leca than g-propexphone. It wili como into she maricet éuring 1902.

Sumarz: Dusine the paporting poriod, teotins vao cozoleted or in progpress ou 10 cópounão. Cno of these nas droppod tecatse of high adáletivoneso. Tuo (I-D-a0 and I-D-22) are yronioing antitussives uith little or ro addiction llabillty. Poue (I-k-1, I-N-1, I-N-2 and II-0-2) beva preeiso of being anslgesios of low addietiveness, and ons of thase (I-x-l) is caning into the open mrket. To (I-D-21 and I-a-2) prosent intorostins dissociations of effaat worthy of Nmther investications.

FLANS POR FOEURE:

Incdiate: Conplete teoting on I-D-21, I-Ri-2, I-N-1, I-N-2, and H-G-2, Investigate N-allyl-14-hydroxy-dihyéroaorphinono and any othor ccspounda rocomswended by tho Cosmietoo on Drug Addiotion and Harootios, ational Rosoarah Council, MD.

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Lent Ran e: Contimue soareh antil tho Drug Addiotion Commisteo, HRC, MAS, is catisfiod that corplotely adequato substitutos for cocelne aro available.

REPoRES AD PULICATICUIS (durina tho cumont report period).

1. Pracer, H.F. and Isloll, l.; Euan pharezcolooy and addietivoness of Ethyl 1-(3-cyano-3,3-phonylpzoggl)-4-plpepldine earLoxylato Eel (R-1lz2, Diphononyiato). Bull Narcotics 13: (1) 20-43, 1051.

2. Frauer, E.P., Partin, V.R., Volbaoh, A.D., and latoll, H. Addiotion liabilitg of an isoçulnsline analgenio, l-(p-Ghlorphonethgl)-2-sotiy1-6,7-dicethony-1,2.3,4-tatrahydroisoquinol1no. Clin. Marmasol. Terap, 2:(3) 207-299, 1961.

3. Frasor, H.P. and Voltach, à.: Te addiçtaon llability of Alpha-dl-aeotoxy-4,4-dipudryl-ć-methyloninoheptane liel (uI-7667, A20 1-C-85) and G-Acoty1-3-ethozydiiyaronorphine (NIn-7te3, ARo I-4-X). Bul1. Drus Acdtotion and Narcotios, Acd. 2, pp 1-3, 23rd Neet., Comaittee on Drus Addietion and Hercoties, Mo, Vaohingtoa, D.C. Natl. Acad. Set., l9Gl.

4. Frasor, H.F., Eoslg, C.F. and vollaoh, A.B.: Evaluatlon of carisoprodol and phonyromidol for adçiosivonoss. Dull. larooties 13: (4) 3-7, 2061.

Harrbe r10 Letel Dipsotoy nautetlon Nosucreh Coutep

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