ABSTPACTO Cr@' !'=-SUI@T.'.@ Sinep. St@irt of T@.t3 porffbn of thz suf-.,-..ary p Du covers the''ertod '('r-am t July 1",;PSIo -cz,,nber 1'-'4. As stated -,bove T the' obj,,@-etive of the projcct Is to synthcfic drug wol4tch would be as affecolive aact as sat'c from the points of vic,,j of human foxicify and a,-.'diction liability 2 as Is eodeinz. Althouch adequate synthetic substi@,utes for morp,%Ine arc available.,, such a sulistance is nectlcd becauzz no such dru3 of the codeinc-type Is knok-;n. S c,.,e n t y. per cent of the needs for narcotics are for codclne rafher 2 than mor,-)hlnz. T.@is r..-,cans fhaf the Unite--I Stziil,--s musil co,-ifir.u'-. to and stockpile opium unfllt an ideclu,:! 14 u- pynl ih-.tic stibstifu-@l-. -for cod@in.- has beca '2She role or' tNe Addi'c-flon Re3oarch Czn#ler In thi-, tnvesill- ,gati3r, concl.@t,., of,thz cycslcr.-,nl.na't ton o-il tl-.c ad,-jilctive propertics cf n--w druos. Ti2ia e-iatuaflon of tFe anai.,7ealc and anfitussiv-- effects r-.-ist neccssarlty be made elsev.@cre. The r-.c@hods u.,,cd for t!ie addiction flabillif-Is of new anatc@--stcs 4aiz bc,-@n dzscr2ibz-3 In de-t@all i.,i tiiz pr.oj,,c@ dezcrii-ii-.ins and in @,r::@vious procrzss rep,.-r4's. ue- s to be ctudil-d as synfhetic f@,-r co-4clnz are C:r 2 r @, Iz c s and t'arcoi ic; olf Iona I -zarch Couacil. ri u- h dr-jos a rz r e cc i@v-- d a t t li,-, 1-,l Add I c t I.-o n R z s @- a r ch r. f e r lhc hu.-,an of f,%c cor-.p,),jiids Is L-,y detc,,-rifnir.,, varlot-,s eoses o,,i blood rcspiratory minuile vatur,,es body te.-.iperaturc,, pupl I lcr,/ eizz, Folio-ting coriipi.eflon of t'lle basic pharmacc- logit-al viork, c-11'1'ects of the drugs on thf., behav'tor OT addtcfs are evatuatcd by &drlintstering 'fr. d'ses based on flic results obtained/fhe pharr@aco- t@en 0 toeical exocrlr-.ents. IT'.thc drug 2Induces bei@aviorat effects reseriblina those seen after administration of morphine or t codefiicj, It Is very likely to possessaddiction flablitty. The ability 2 of the drug to reltev,- or to prcvenf the a,.,)peerance of Syr.-pt'oms of abstincnce from morphine ts next .,@tidled In p-tic-': stro.-i'gly addictcd @to morolitne. If f.@z 2 erus under 'test relieves or suppresses abstinencer tt is 'fo havc a--'dicil to.-i ttabl'sity. In su-h the datc of the drun...'ur,,-,;er tesf which Is required 'i-o retlevc or su-2prcss 41!1.z of ab'stlnc,-ice anc.? t,%c dec,-i-ee oT ,)r-suopresston of abstinence are Indices for ccr.-,oari3on -la rd drug, codzine. %7 li .,hen an cspcc2lail,/ promisin@i drug becories evallabic, s j I -z d- b -/ f!i -- d I r c c S4 a dI c t I o n t c c h n I cThts Involves i z r z: t I f a s c - n cl. I i do @., c s t o o r n-- r d. d I c t s a r 2p -z r o o -le r a ri I n g b c c n 30 to l'OO ull ar- y:; D r r r..ieasurer:.e. carried oul- to dc-ecs' and ey-aluate the developme,-.f of folera c,. a b r uo y a 0 b 3 3 f 0 r r rj - s ar, e, I 'T;, ei r a d - ve p,-ne r. o a b I n n c c s @Tip t oris -2-,a c4z 'uring period I July I'Si f-o T,:c Dc-ember ar- febutaied belo-.t: , gt I.fT IL IT Y Ar)D, ICT ION L IAD I L ll'Y ToX IC ITY (,71)ss IB LE OP LJ3 (Relative to Coe-cint7) (Relative 4-0 fie L,,--orphAn Mucfi flighe.@ Greater t --rjrrimt)ran r of Le2vorphan Higher Greater I-F i7ould be ethl LI:3 ed f or ri I I (I pa I it ti)ylmcftiylatiilno-I2 -1 (2t Higher n ,ji iii len-li But-i-ene il 121 Higher Greater l') n c It I c n v I 6 u t - I - e n e 2 Lower L6 we VI .-'L-Ir or,.o r a n (3-Mctlivl tower Lo tic r V-@ r v I)i- (i-,i I s i.-)g f o r 2 C u,-i It cl@t-ir of D,.-xi-ro,)Iian) I b I Iii-les dimethyl- lilutier Soev2illat less r,)r paln i-elicf ttinoethyl Voicrate SI ICIlit Pf)$Sll-.)Il I I- I (i 2:2-t)t fienyt-4 dime.thyl- Hictier About equal ..,Inoctliy Valerate f,-)r.paiii relief I 6-2.2.i.Dtpticnyl-4 climcfhvi- %Some v.,'Il 8 I. less Slight P-.)Sslbil I t I c s a,-. lnoethyl Voler@.te for p2ain relief Slight r)c.,sslbll ltics ethyl 2-,,....Dtphcnyl-4. Higher So ml- tvb a t leis 7 f @)r pat c I IC @c' '9"1'f-.,.cthylamlno butyrate n r -OX IC ITY -L !AB I L ITY oss I B LI' DR,LJ13 ADL) ICT ICN c VCILITY (Relafiv2c to Coclelne) (Rcl@tlve to C(3detn'c.) I pli aI -hie t li a do I Higher Higher 1,,-) n c t a -d I -NIIC t h ado I Higher Loiver 2 Lln 1. no v@n rl-Dimcft)YI"3-ltydroxy- Higher Less :',rpli Ina n LItiLnovin Some Villa t 2 11 C r Possll>lc for relief trobinan':@ of pa In '@ixturcs (1-10, I-Sp 1-3) i 2 About equal V c-- r v I lri I IL c cl I-,'%Jlorpitlne and 1,,'orphlne"."-. P,)Sslbillfies A @-4-Diphenyl -d Ime t b VI am lno-- Higher Sofne tvh a t. ti Ili C r @'(,.ry dcf In I te none-3 P,-) 8 slbillti; s f r 2 cour ,n ri Pa.. nrelief %VIA r!. not onfiretv completed during period to I.I...cy4 L;-Iow for further detalls;@l Cb 0 co C:; 2 C -O fq < C'@ 2 CL 11 ii -to C4 n a fn -t- 2 Z 40 -t- -4-0 %* -1 ri to 0 tv 2 'k) cr CL A 0 2 0 ' il@L r a, . - 4q 2 CL 0 C& 0 0 2 cr 0 'O 0 0 \r- cr 0 CL C 0 i,@ =r J W.) 44 0 2 :r C% CL 'U a to -tl C4 .14 -41 a 0 0 CL 2 0 cii ei X :3 Z141 2 O- C Lr :3 c@o 11 i3 2 (L X --i $at C 0 n. CL (a 40 n 0 2 .,t. 44 --O -1 :a, n 0 401 0 2 co :7- 'U 0 2 'U 0 0 n -0 co 2 o ib < L). zr D :3 cr 2 (I Cb CL :3 -I- 0 -3 ei 10 0 CL eq 0 Lq 'e) .0 ..) (4 - C.L 2 0 -r) 0 -4- 7u V4 41,@ - a ,.,N :3, 2 C4 C: C 7J 'U 0 CL (a 2 le 0 ico - f 0 C) -1* 2cr 0 :71 0 n 0 0 Gi 0 0 C 0 r2it 0 CT 3 (4 -C - r$ -t. 70 - - op 2 n o =rl -< cn 40 I'll -t- 11 & 2 C4 -:.I 0 0 0 'O 0 'U 20 C W 0 X 2 cr m n ei, :,J Po .14 0 n -42 4A ri LI$ m cr at 44- 2 -C n 0 cr m m CL 0 11 -r 11 - 2 - n O. -1 - n C: Go 4A 1< ::r CL 2 Q -I- 3a C ti 44 44 0 n C). 2 -i Cb 0 O. r.L C4 0 Go .41 C). 2 tq 94 0 2 O- 0 Cb C Ca 7 0 (L 0 '7'iis rcprczenf3 another possible for codeine since tt Is In act! ve.use I n G@e r,,na n y as a cough Sluppr4issanf-* Ft.,rfhcrmore, J*f shoijfd, be a nild an,519estc cnd I-- castl,/ a yqfhcz I zed. y .3. Benz I nio r,,-.) yris4yl cster. This drvg 2 which %7as dev-, topzd tn Fratice,, is ..Insoluble In water aind ly a can be Injected on s oral'suspcnsion. For this reason, 4 all work carried out with the drug has been by the oral 2 route. Doses rangtng up to 600 mg. orally did not Induce any def In ite -mrph Ine-I lkc e-#:'fects In -lonfoleratif addl@cfs. Transient skin eruptions consisting of blote-hy erytheno and urticartal v.,hr-.ols wer-. obs I-rved In bo@h of the patients who reczlvcd dos z drug was co.,.lotefcty inzffective In SUOprZt.3ing absfinz@icc- Tror". rior!,a!iina. 'I e dru- Is not rega.-d-@-d @-fts a -romisl,,ig since It Is not a true synthetic, has too hio.'t foxicifvp and Is probably therapeufically lnerfe 4. B c t I t h a @o I In cicses renoing bcfwccn 30 2to 100 ric,,. o,-all-,l f-,r subrt.,#'a;-.couslyp beta-di-r,-.cfha-Jol did not It of a',.-s'rirc,-icc froin,rr;orp,%'inc In f -o r. I i a .1 1 2d n If Is, j U,:@,,- a C,o n a clinical c!afa avallablz on lh-, poss-i'clc -talue of' be'la-di- a a s a P. a a 14 u s I c a IC -a -I s 'el IC 4 as a syn.-it present T h I s dr 0 hovic Y;z r j, c a s I y c -n, Ica I ce.,i vc r..t I b I cto a drug with ver,/ hi-.@ adctlcf ton lab I I I t For rcasi.->n, It Is u.,2rllkcly ihof It would be reeard4d as belng a safe substitute for codoin-.. 5 Addiction liability of Natorphine-i@.orohinz II-IOI Llixture. In previous If %,ias sho-xn that 2 mixturzs alorphine and tr rphine vere not likely to be abused b,/ of N 0 drug addicts sin 'm cc O.-Ph It-ie-induted -u:.Dhorta to effcctlvely blocked for 2 hour: by the Natorphine and since T.njcctloa cf such a mixture -xvould precipif ate abst inence In add lcted Individuals. Pr--vious direct acldiction experiment's @,vith fhls I , d 'administration o;2 very fil,.gh do=,3. ('*addicting mixture tnvo Ve dose sche4@uic'). N@o ln--'I@orr.,aflon was available on of 'AL '.-Acrapeutic doses chron Ica I I v. :Fo r th I s re&-i-ciT, (5 poll lenf 3 I 0 warc C'i -or, line r@-0. tlalorp'iire ever 'our y hours f or '50, -da ys., ,f ter rih ic-h t'ac 0',-ug' -.ia s w I itidr,*wn 't"he ur,pleasenf side er-fec@s no,4cd with addic'&-ing" 3c'.,,idu'les eid r.of a.@>p-ar c!.-ise scil,@duic. Dlfinlte., mi,id absfi,-LC.'ICC, appecred folio-aing ml-turc) a-# s, pic-i-A Olt' zi 'D 2..i I n I s f r:--t fai 10 c r f o -,j r o u,- s T- o r C' zi a '&- o t li c r c t c 2 'T j r c I s al y or In one sens.3 the ad-,Al 1 c f Io .1 I-ab II I ,s =or ase. o r ;>h I n roh I - - x vr is ra0@hcr 1%@y Is not rcoardec! a pro.-.iisino Su-bsfitutc for coecine. Fvrther,mre@, if not a t r tic t yn h c i- Tc 6. klorph inc Antagon?3t3 Cther than @@.alorohine. Is beirg-uneertakcn In the hope of developing a r,)or,,-.>ht:ilz anta!gontst v.,bich Is orally effzctlye. The coinbination of such an antagonist 2 tvlfh a svnthztlc such as methadonep or Racemorp.@an,, might decrease addiction liability and,, f@-crefore, be regarded-as a po,sslblc substitut'e for cocj'ctne. @:7ork wlih four stnthette ant'agonistl.' has bcen partty cor@-platedif @@(a) Levallorphan. This Is the levorolatory I,lo,-.ohina.,i analocue of @4alorpi@lnc* The dru-0 i%.as 2 bec,,i stiown to be an eflr'cc;fiva antac,,Onlst to -io,rpht;-I.-. and Racc,r-,irphanp bo,th subcutaneou:iy an-., oralf,@a The antagoalstic effects 2 persist tonoer ffian d 'thoze S e r I a u-s- I c 01 .u rcae-lillo#-#s may oect,,r' wif@@ 2 of nausco: vo pr4zcloij'ouS dropt' In blood'p!rcsosure. To@@-ic' -,ff'-ts of' 4!le cc,m.-pou,-id In dos,-$ whic,@ u-slz,-J In2 riixfures ar,,, n,)f of IOU3 ccns,@qu-znc,@-. -1-Ince fhz drug Is cf-k:'ec$'Ivz c r a i i r cl c n s s 1 b 3 c r c c-le-i nf 2 t r z OT r o C dcxf-rorof,3tory i sor.,.er o.@ Lava lor.-,,ian A 4 linn consti'4-ucnt u c r t e r c f r c n,:; a r o ,n n a a f a t C Le va an. Th Is. comonund I s tha @3-n-@-thyl ether of, Lcvailorphan and was -4'ound to be effecflvzp either -@ralt@ or subcufa,7covsly, In anlagon:i-zing flic2- efr'z-- 'Jr- s of riorphine or Paceriorr,,,%ar,.. Untoytird sldc effects appearad vi ti'l clo scs grca ter t hcn 5 @@"*h I le a def I n I f e poss ib I I I t y as a constttucnt of an anfaC;onist2-anaIC3estc nixturej, It possesses no advanta-z.s over the parent compound, Levallorphan. id) -3-Hydroxy.-iN-Propargyl.tl4orphina4le This c.or&.pound Is of espectaf Interest since It produces analge2sic -effects In mtce@@which are equal to those induced by meparidine. Despit.-- this, the eru- Is an ef;lectlye zatagonist when ad,-..Inlstered si@bcutancousl,/, but 13 far IC$3 CfT'CCfIVC WhCft 2 administcrcd orcllv. :It @,at t,-en shc-@,i,-i to precipil.*;,,-_-- sl-lptoris of abst In en cc f ro,-.i r.,orprh in e In a ad I p&f 1-nt& Ihcrefore it is ro.4 11'4e!y f(@,,bc abLz@-,d,b.y If OT,fcrs Some promise as beir.- im possib".c subsfilute for codci,-)c T',.)r .he relief. of M.I'id palho I 1-3-Acc f I.,ior-norph ? na n compound is also an-cT"T'ecti-.,c arsla--,cnts@ whcn inj-zctcd 3 ubc uf a n--.Dus a.,, an7aoon T:f -ani@ l@@es IC 2 a s p,-o.-i s nC4 a cori f Lt-n m X r S ,cc-,! Ca y 7. t,,r@rcotine. co,,,Poundi, fcov no'T C$' n-,ir5phlnzj Is deri@-,-j ool,--m, and I,,) no';,' beco-c I n h@.man and animals. If f-h Is Is conf 1',-ricd, the drug ml Nt a@ possible substitute for codeine as an ant-ifusstve and would, thereforz.. have the ef-rec-f of ex.end?nC. th-. suppl,/.of codeine derived from opium. In doses-ranging up to 100 mg.$ either orally or su!:)cutancously, t,%c compoun,,, does hot Induce morphine-like effects In nontoteranf former 2 morphine addicts. @b untoward FOXIC effects i@iere observl-.d. It appears to be totaity devoid of any ability to suppress synptoms of abstinence from morphine. This co..np'ound Is, therefore# rega@2'rded as bzlrg very promis-ing. 8. Dlhydrohydrohydroxyri-orohinc. Tt",I& c;otrpo,w,nt Is the morphin4 analogue or' eu'40'dal t@,4,lhydrohydroxycoc!-.Inone). In dotes of 22 to 3 rig,*' subcutaneous I y,, '.f induces rarlt;-.zd r,,orphine-It@.,c effects I nc I ud I c upo-r-c r I a It rclicv.-s anJ Su,aprcsscs astinence T'rc.:@i mor,-.2)htne c-.m-)Icfely. lis addicilic,i ll,'abiltily and toxicity are far greater than 'Those of codeinone. The drug Is, therefore2 not a suitable codeine subsf ttulic. 2 V p b c n o n - c; A, J z 1, 2 d 2-proplonoxy-3-rlct'-Ylbu'a:-,c T'.i t s compounc.1 %vas- I y c.-i and 2 t'arc.o.'Ics. by fhc Comniftce o- C)rug Adeic'i c @l i -7.,a r - 'o a n o r c I $,-i i c I 1 n a this d. r t,.- -;a yhave'anaf--!cslc pro-erti@3 indicaf,- f,@:3iL r c r c z-:)rox 1-@.a Y c,;ulvalcnl a@ very im:%,->rtant c;lru!g s 2ticc- t o @4a f n z,- 1-@ 7 ub s I t u f s for codetne hav-- bee n a.-, t us s ra he r than ano I oz's t c-5 So f a r. o.,i I pret nfne-ry f,,-txlcol-,.-It !r,)uri,-- currz,,if re:) -or o:criod) H., and Fr,@s..---r, H - Ic 0 dcl I c I r of L'@erivat&lycs tabsfrdct). Fcdcration r4EP02TS AINO P@MLt3NTICVS-* (Coat td), 2. Fraser, ti.F.s. rlash., T.'#-,,$ Van Horns G*D*., and Isbell,, II.: Use of &@,lotte Effects 1,.l E@valuatlr.,g Aoalocslc Drugs In @;',an. Arch. lntcr2nat..dz pharmatodyn. et de therap.0 9f'io. (4) 443-45 (Aug.) 19540 3. Reports to Co..-xilffee on Drug Addiction and t-4arcuffi.-si Nettonal Rzscarch Council.- (.,a I;qo r k 2of r4it.,I-i Addict Ion "esear,h Center, Aanua I geportv 22-23 January 19S4. C:ontal@-is r-c-port on the addictio.-I ltobillti4.,t of Oallfic-morp.@t-,ic -nd d 2-r4-Dir.,.-tt% yr.-o r ph I n a n ixturcs; a YI y .. d 't and d Y7,i I c r a cl IEthyl 2,2-Dilp;lienyt-4-Di7rcthylarilno- butyra@c; 2 and d all,/Inormcrphine; aid Inc b Ar-tdiction Liabit "-y of 1,@arcot C@e-. f 0 bz (c) f y c f r a y -r -:@'i v --'r @D x Y 9 i@.a r pn o n c2 Cc t c@ b,-, rZ')0 H.-, r r Director o7' 2--scarch A t a c ns