02 sum s na Tum,,,s Foq codznr:i, F.-arris Isbell Nrl-M Addiction Ptasearch C,,nter,, PIIS., T.4xingtono Ey. H.P. Fraser, A.Ltkler,# W2.R, I-lartin ard A.B. li;olbach 101-149 XAon." 21-61 To davilon syr.+.,hotio for codai.".e-,4hich am as e.."L"fact;ive az co,4%--4.ra for mli--t-I or pain, cou-h and di2arr.h-.a,, -but whieli -.Iiwre leba addictive propertiez. T@3sting of tl,.e addic4v-ivoroza of fiva potential codein@-- oL,bsti,@w,utes ims comletod durin,!; tho year. Cne of these., .-o-isoquinol 2 h-yd in ial vas.de-cribed in la3t year's ab3tract. F=ther testing of th4ts a- nb zupror;@,,od previous- result".s .-- it h,,,-s li-,%-.tle or no addiati,.reness even .Yhen gi,v,,2n intr,,,-vano-usly. Sin.-.a t-aa 2co=po,-,x..tl ha3 bc-.n r.--port;,--d to be as ef.-60ective a3 eodei= as an amigesic, it is of great; C-Di=thyl-3-phenyl-@;?-p,-o-oio.".o:,,7 pyrrol-idine Hal (I.&O-15 also prove2d to b-e lesa addiatire th= cod.-ine, Tl,.e ..%nnIgesic offec'$.-,z of 1-0-1. hov.,overp can be questiox-ied and clinical toxicit7 is lugh. Ethyl 1-(2-Carba=ylothyl)-4-@.r,'.Iienylpip-oridine-4--carbo-"-,Y-@ late 'i7.cl (T-D-20)0 an antit-azsive agen"%,.,, iz devoid of addiatiN,e-,ioss. Ir-.to oth-r d-"L-7 s., 2.,2 (I-D-@:1) and d-3-De-,-f!@,. thyla:--ino -1., I - Courcil@, fe-.It that ad@--quate sub3ti-tul.--aa for code:Lne in all therapeutio.@applic-ations are ava4.lable. (b) Im-,-*--diate. Dru,,P-,, to be test--ad durl-ig tl,.e cord-r,-, ye ar .'Lnt.-lut-la: (I-J-3) 2 -.oh^-n7lindane H,-,i l-"ydro.-.njotho.Kyetliyl-4-phenyl- 4-propion-71-piperidine E,i' (a) 11. P. ,r-raser and R. Isball@ "Aliu,,ran phar=crolo,ly and addiet.4.van,.m3s o+-" zth7l-!-2(3-cY=0-3,3- Dip','-,xnox7- -bicst 13 3.ate. Bul:L. r.-a=o L:9-43, (b) H. P. L7raser, W R. V,-artin, A. B. Wolbach and H. lzbell liability of en lsoquinol2ine analzesic, 112 3 Clin, Plmz,:r--acol. ",temp. 2,9 !P37-299 E. F. and A. B. Wolbacho jr. (1961)s "T:ie t4 addic .on liabil.4,..4v-7 of Alph,,,.-dl-3--@acetox.7,-4,4-diphan,271-6- z.^.t,h7la-mino'hopta-,i,a hydrochl6@,:;Ide (','.-=-76"7, Ai'!C.'r-C-,--'5) 0 and etyl-";4@ -e- dlhydramorpl,,4,ne -7'23s AMC I-A-38) DIII-1. 3 Add-' ation a,-,d I-arcoties, Ndd. 2p pp 1-3. 23rd Co=. Drug Addio,"Uion P,..-id Ilarcoties, liatl. D.C. Ila4wl. Acad. Sci. 1 November 1961 c poR (pro 4act Da3'ari,,ntion) F,OT-tiaL-,t to th-, CA'a0 f Por nt.-.,act the National. L-.ztit-at,,2* e '.@,lental bes been carry-4,nS a project uith tha cb ,or discover4-rS i4.1a substitaw-es %Oor acdeir-O WOUILI Ca mspeat to to@@e4ty an as aaf2e a-% d addicti_on and -,thich also 't.-iould 1:4 -3 eflootive ao code!=o'as =.,-idia=haal =d ts Mae pro ,esic *Zen c haa beer. partl-7 b7 funds f..-cm the Cf4A':Ic* of liaval conzti'.,-utes a -ocriest 0&'o*- -ene,,ml o,,ho the proj@Dat ror tl,-,.,,,p^-r4-od I J,,xl7 196P- to -0 T=-a '@zitia:L:L7 und,,--..-talmn becauee cod-:aim was e,t* pro ,@.,a:3 tho rost t.,dde:Ly used z=.-Cotic in both eivill,@n azd SLnwo code-,ir:r3 io derivad from o--rium, or =d,a fr^.= mot-p7ciine fron it-# v,,as necerza.-V for tt,a Statat It-.o stocicpiie o-.:)I= ox-d--r IL-o in-.ure a a.,Pe 2 o AA a,apply of codei.nel> :Ln the event of war. 2-v 1= Ad,,.Uction rasea--ch C@antar were rot to cal-117 out th,@A uork w:ttliout L42,tu-thor th,.& D--rart=nt of 2.0 i;-,.17 70 o m,-@ o urd a been In t4,-.a :LO Y--ars t;ho ria3 b.--en o,,,.mrating, ILAvo nor-L,,nd,,U-rtive, 2 and .i-ere devoloped.. n,,.-w analgeaics fi4-th add4-ct;:Lvenoos loaer Wa.,uvi of codai= have alao been d,2velop,2d. 7--icia OZ-0 A-.p.-opozyph-on-.% a-,id the Imo,@-m as Dlp:,iorozy:Lato (R-1132) is a potent c-n'-6-id4-arrheal cL,Zent which is less addicl,,-,Iva th-= code-,iw. the cu.,-rer.,-.t ye-,4r tb2tt work on the isotdzoline derivati-Ve wa-z co=pleted* Aa maiitiomd in "..azt yearli-3 r.--ort, tUa drrig iz or Z--eat int,.-.r-4st,, it i-i =ri 2 Lhim or codaim, :En =n It doets offoot.-.,., it is :Lneffect-.,L,70 ab*.tin-nee from ard dc;e3 not areat@.- In a, tih-.n g-tvan eh-"cnicall- Li 2 dozes. Nonet4^icless it haz beexx -a. orted to ta a..3 offect4..r,- codair,a :Lvi in alin-4.ca" 'Ur.f or L"O-a=- th@-- d--L"s 4.z 3,4lta7cle On.,,L3' for oml =a cx --I desiz:=- bY the earial nuzber c., oun :cc@..i wa3 atudle d- durin,;@ thO 7,ba. :E',, Iduee3 =27 u Partial fo,-,-ob- azdicts Vnd i3 z2,nect@r-L-P. of mor;,, ko of.,,CC.4's In =re potent wh-zn tuan wl-i,,;--n gi"-n inti-avcno=ly* It from moz-.Pbl= tO cn2.7 a Olitr t d,^-Sx@ee, -.a a;3 @- 3tbatin-ance =h On di--O-vt P-ddiat.41@.0-&Ip t@@7.ic --.-Aects cauzed all pp-tien-16,-a to -erom lovd but its toxicit7 @=7 p---eelude clinical use, 6ompoard :Ln tho series d--zsign-at@ed b7 the sarlal riurber :C-D-20 no fiubjoativo afre(:ta of the. roa"L,-m of It did not 2 It thercfote i3 not an Compotnd tL,.td may A-'e,--)resant t'-,a t@Ui-d =ef%,,a &-ititiaz;s:Lve -,ha of t4lie co-.-,,7oun.-Iz lmo= az I-D-21 (a mth.---dom derivativ,-.) arA I-C-26 (a dsr:Lvative) bo-lv-h pi-oved to be -"t loaz4o,* aa addictive a3 cod^.in-. =d b^-on dro,-,)n-*.d rrom fu.-t!,.er co=.tdev--ation :Lvi tho progr=, 2 %!,led for of ",-,he Al"v,,hough a S=at doal of been u-e 5,-.ill pouces-. no ;-4in;@,l a dniz i.@i-iich :La aa of factiva ard aa codain,a for- a-li ti,.o 7a-,7oza3 tor r.),,4,4Ach codeizit,@, i.,-3 -,in-ad. a:,-- r,,ot as az codairto in i,-.dazing analge-31as and both a-,o ==la toldc* :@;3 zuitable -or*ly for oral u.,,.e, Tr. additi-n da-ca are UIC4 noodad on t@he dist-"ib ,cn and fa%',e oL' codaine a.-,d vu,-rious c-,%mt-hatic drig3. Bet-.--aem i July 196--i and 30 Jun@,-. l@Z3 we propo--e to t@^- a V,,-ia 02.iriical of f o-,zr d.,-,ag. 2 a@atitusaive luix,,rzi a's 1-D-2"-:" irdarz la-x-min az 7:-Ii-1; a,.zd a ben=, rpl-=, a:i 1-11-2. :In s*wt@,d-i@A.a of vrlll be oa.--r4-ed out b@2!causo t.,hi4-0 t,-anqu:Lli=r h-as b.,.%ea to bN-. az aa in pz,.in in =n. Ir the which .1@6a on c.-der, be a o-.,, 3 av,.-,@ble,o u-ork vlll be initiat@ad2 o-,% 1,61-,e =taboll3m of azid o -vanvaally th-I a work wil-1 te extended to the =tabolizr, cf CZ-.; cl--.a of tho a,.%tit,@.qsoivos 0: th%? t7ge ,vzthodi u;sod a..-e starda.-,4. aA;IdicAwion 3 t inS t -h a- --I- a- 0 @,@ tho 1=-2 Ad@.-I..qction Fasear-.h t-asts ara acc,-ip-'V-od a3 s-tan-@lard-s for 1 action b-,;w tI.,.a on Drus Addictioia ar--l ha."e deserl't@@d !.a prL,-v-1-ou-3 41 =thc,-,;-3 to be' uned arft. =d Involve sec=tilm, Of thD and ',;heir matab-ol.-',.ta5 by with differcrt,.'6al at ",xiz)ua pE2$ t.-om i=purities bZr ch,-omat-%Svaphv ancl& idar@,@.=cat.*6cn bv a'variei,-,l or e-nd plioto-=t.-,r and cn Cip D;,. 0,.O the data 1,= bee.-% co-,te--ed in To IOea4,4 Cr Pr,, t V.ork w2i'-Il be c-at-@ried oai,, at the l,@za-zarch r4ntuc,%7. providea t:!,.e t-.o neceezarj, faeilit.Ale-s for tha t,,$Te cr work to be. untl-o (1) a y.@,ol of %.#i-2^nta u-111 volun*waer for expc.-iments with d-"uazt and zt--,-Ict environm,.nta-1,@. oC dz-i.@z3 than t.%o o u-.,x,Lftr st@,.d7 :Into experl.=n" 2 le t-a bioc'.,wzl-aal facili"%"4-Cib ara caso ava:Uab"La, V;ork ULU ba ea-"-"iod Cui", UlLtee- tli-e cil.1 Ea=-Is T-aacarch Thia 6 h-ad il.*fy vea.-s in r,-,a-c-a.6--ch on a-idictio,,i ct-,,.d tza-, a-n ass i:sted b7 tito e.-.-.oerlarced b o th c arA Abra:a= WiL"I-ar,# an ard have =rq ptib3-.-iezti=- 4, vhom dore mzea-"ch in addioti fte.-,txices oP a tic@chominti, A I u-a i, d @i,3t are al@no and the so in 0-_- .^rat4 f th,o hospi'l.,ai aL-d".@, M-C"e th,,= ralne years* .a The cost i z -z. 'Li onor- Ir4he a"v-taci@od FArris '..rzbeIZ, 2.1,D,