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TFE ADDICTTON LIARTLITIES OF SENTHETIC SUBSTTTUTES FOR CODEITE

Harris Isbell NINA Addiction Researoh Center, PHS, Loxington, Ky. H.P, Frasor, A.wiklər, W.R. Martin and A.B. Wolbach 101-149 NAonr 21-61

To dovelop synthotic substitutes for codaine-which are as effective as codoine for relier of pain, cough and diarrhea,-but which-have less addictive properties.

Tasting of the addictivoness of five potential codeine substitutes vas completed during the year. Cne of these, 1-(p-Chlor-phenethy1)-2-methy1-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline Rel (I-K-l), was described in last year's abstract. Further testing of this agent supportod pravious results -- it has little or no addictiveness even when given intravenousiy. Since tha cmpound has bocn roported to bs as effective as codeins as an analgesie, it is or great intorest.

1,2-Dimsthyl-3-phenyl-3-propionoxy pyrrolidine Hel (I-0-l) also proved to be lesa addictive than codeine. The analgesic effects of I-O-l, howover, can be questioned and clinical toxicity is high.

Ethyl 1-(2-Carbamylethy1)-4-phenylpiperidine-4-carboxylate Rcl (I-D-20), an antitussive agent, is devoid of addietivenesa.

To other drugs, 2,2-Dipheny1-h-(1-[4-(N-piperidine)- 4-carboxamidel-piperidine)-butyronitrile (I-D-21) and d-3-Direthylanino-l,1-diphenylbutyl ethyl sulfone Hcl (I-C-26) proved as, or more, addictive than codeine and aro being dropped from further investigation.

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PLANS FOR FUTURE

(a) Long range. Project will be continued until the Committee on Drug Addiction and Narcctics, National Research Council, feols that adequate substitutes for codeino in all therapeutie.applications are available.

(b) Immediate. Drugs to be tested durins the coming year include: d-Phenampromid (I-J-5); 1-2'-iydroxy-2,5,9- trimethy1-6,7-benzomorphan Hr (1-H-2); 1-Dimethylamino-3- phenylindane Hel (I-N-1); 1-Kydroxyethoxyethyl-4-phenyl-4-propionyl-piperidine Her (I-D-22).

CURRENT REPORTS AND FUBLICATIONS

(a) A. F. Fraser and H. Isbell. (1961). "Human pharmacology,and addictiveness o Ethyl-1-(3-cyano-3,3- phenylpropyl)-4-piperidine carboxylata (R-ll32, Diphenoxylate). Buli. Narcotics, 13, 29-43.

(b) H. F. Frasor, W. R. Martin, A, B. Wolbach and B. Isbell (195l), "Addiction liability of an iscquinoline analgesie,1-(p-Chlorphonethyl)-2-cethyl-6,7-dirothoxy-1,2,3,4-tetrahydroisoquinoline." Ciin. Pharmacol. Therep. 2. 287-299

(c) E. F. Fraser and A. B. Wolbach, Jr. (1961), "The addiction liability of Alpha-dl-3-acetoxy-4,4-diphenyl-6- methylanino heptane hydrochlcride (NI-7667, ARC I-C-25) and 6-Acetyl-3-ethoxydihydromorphine (N-7623, ARC I-A-38)." Bull. Drus Addiction and Narcotics, Add. 2, pp 1-3. 23rd Keet., Corm. Drug Addiction end Narcoties, Natl. Res. Council, Washington, D.C. Natl. Acad. Sci.

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ADDICTION LABTLITY OF SEIESTIC SUBSTITUTES FOR CoDEnE (Project Dascription)

Request to the Orfice of Naval Research for Renewal of Contract MAonr 21-61, NR 101-149

1.Backgroumd Infornation

Since 1951 the National Institute of Mental Health Addiction Research Center has been carrying on a project uith tha object of discoverins synthetic aubstitutes for codeino which would de as safe as that drug with respect to toxlcity and addiction Miability, and which also would be as efractive as codeine as entitussive, antidiarrheal and analgesic agents. The project has been financod partly by funds from the Orrico of Naval Ressarch. Thia description constitutes a requsst for renewal of the project for the period 1 Julz 1962 to 30 Juno 1953.

The project was initially wndertaken becauee codoine was tho most widely used nareotis drug in both civilian and militars practice. Since codeina is derivod from opium, or sade from morphine dorived froa opium, it vas necessary for the Unitod States to stockpile opium in orler to insurs a

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supply of codeine in the evont of var. The facilities of ths NH Aadiction Roseareh Canter were not sufficiont to carry out the vork without furthor financins, by the Department of Defense.

2. Work Accomolished to Dete

Approxirately 70 gompownds have been examined in the 10 years tho projeat has been opsrating. Two nonaddietive, antitussive drugs (dextromethorphan and narcotine) were devoloped.. fhree nes analgeaies with addictiveness lower than that of codeine have also teen devaloped. Eese aro ethoheptazina, d-propoxyphens and the isoquinoline drug kmonn as I-K-l, Diphenoxylate (R-l132) 1s a potent antidiarrheal agont which is less addiative than codeino.

During the current year ths work on the isoquinoline derivative (I-K-1) was conpleted. As sentioned in last year's report, this drug is of great intorost. Chemically it is disferent from eithor morphins or codeins. In man it does not induco morphine-like sudjectiva effocts; it is ineffective in suppressing abstinence fros cmorghine; and dces not creato physical dependence when given chronically in maximally tolerated doses. Nonetheless it hao been roported to te as effoctivo as codeine in relieving pain in woll-controlled clinical studies. Unfortunately the drus is suitable only for oral uso because of insolutility.

Project Jasorip mn

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A pyrrolidine compound desigated by the serial number I-O-l was otudied. during the year, It induces cnly a partial spectrum of morphine-like effoats in former addiots and is more potent ehen given orally than when given intravanously. It suppreasas ábstinenca from morphine to only a slight dogree. On diroct addiction, toxic effects ceused all patients to withdray from the experimnt. The drus therefora has low addiotiveness but its toxicity may preclude clinical use.

Another éompound in tho mpsridins sories designsted by the serial number I-D-20 induced no morphins-like subjective effects regardless of the route of acninistration. It did not suppress abatinence. It therefore is not en addictive compound and zay represent the third useful antitussive developed in the progran. Two of the coapounds korm as I-D-21 (a sathadons derivative) and I-C-26 (a methadone dsrivative) both proved to be at least as addiotive as codcine and hava teen dropped from furthor consideration in tho progras.

3. Noed for Continuation or the Project

Although a great deal of progreas has been mode, wo still possess no single drug uhich is as offective and nontozic as codsino for all the purposes for Hhich ccdeine is uaod. d-Propoxyphene and ethohoptasina, are not as efreotivo as

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codeine in inducing analgesic, and both aro mora toxlo. I-x-l is suitable .only for oral use. In addition, data are needed on the absorption, excretion, distribution and fate of eodeine end thsse various synthetio drugs.

4. Work Pronosed

Betueen 1 July 1962 and 30 Juno 1963 wa propose to tost the clinical pharmeolosy of four drugs: d-phenampromid (I-J-3); another reperidine antitusaive knowm as I-D-22; an indane knctn as I-N-1: and a bensmorphan, kown as I-í-2. In addition studies of levomepromazine will be carried out becauso this phenothiazine tranquilizer has boen reported to be as effsctive as morphino in relieving pain in can.

If the gas chronntograph, which is on crder, becomes available, vork will ts initieted on the ratabolism of codeine, and aventually this work will be extended to the motabolism of I-K-l, doxtromsthorphan, and one of tho antitussives of the meperidine typa.

5. Hothods

Hethods used are standard adaiction liability testing mothods of the MIMH Adaietion Rasearch Center. Tese tasts aro accepted as standards for legal action by the Conmittee en Drus Addietion and Narcotico, National Feseareh Ceunoil, and bave been dascribod in previcus project doaoriptions shich should be connulted for dotails.. Te biochemical

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methods to te used are standard and involve separation of the drus and their matadolitas by extraction sith dirferential solvents at various pEs, separation from impurities by paper chromatography, end identirication by a'variety of end reaotions includins gas chromatography, ultraviolet spactrophotometry and flucrescenca moasuemsnts.

6. Evaluation or Dnta.

Evaluztion of the data has been covered in provious desoriptions.,

7. Location cr the Pro ject

Kork will be carried out at the NEH Addiction Research Centar, PuS Hospital, Lexington, Kentucky. Tis institution provideo the tuo nscessary facilitiss for ths typs of work to bs undartakeni (1) a pool of patients rho will voluntser for ezporiments with árugs, end (2) strict environsontal control whieh pravents introduotion of drgs other than thoce undor study into ths ezperimontal situation. Complete biochemical facilities ars also availcble.

8. Exmerimental Persornel

Kork aill do carried cut under the dirsction of Earris Isbell, M.D., Director, Mn Addiotion Research Canter. This investigator has had 17 years experience in rosearch on narcotie adaiction and hes an axtonsive dibliography in this

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fiald. Es will be assistad by two other experianced physicians, Drs. ü. F. Fraser and Aorohan Wikler, both of whoa have done rosearch in addiction and have mny publications. Tho pert-time services of a biochemiot,' nauropharmscologist and rasearch psychologist are also available. A opecial ward for the conduot of these' stulies has been made availadle by the hospital and haa béen in operation for more than nino years. 9. Sstinntod Coot

Tha estimated cost is shosn on the attached ahoet.

Hitkh

Attachment (1)

7023 6

Harris Isboll, M.D. Diractor