.22 -vm a r,! r@ L; LS ABSTRA'T a S I t) ce S f -i r t,-o f@ -I c c f,. This portion of. the turrmar-st covers a pzriod frorii July 1, ll,'Sl t*.Ianvary 1. l@)53. As stated above.' t.hc objective of the project Is to find a synthetic druo which Is as effective and as safe from the point of view o-f hu.-.ian toxicity and addiction l.labli,ity as Is codeine* The d.-ug Is nceded alth@uo,-@ adequate synthetic substitutes for morphine are because, available, no such drug o7' the codeine type ts.avallable. Since 75 per cent of t@ernecd: for narcotics are for codeine rather than for morphine, this means that we must continue to Import and stoclft-pire has bec.-i d-velo,@@ed. opium until an ad,;quate substitute for codeine The role of the Nliv+l A-d6tetlon Q- , iscarch Center In tiirs research is related to studyin the addiction liabilities of new drugs* Thz evaluation o't' an-aigzslc and anti,tussive 'effectt n-cces@.arily rust be made elsewhe;t-,& 1;@iethods used In studying addi-.tion 116bilities of the new analgesics have been describ.-d In detail In the project. an-d ir; przvlous pro-ress rep@orts. Drugs to be studied are rzcor-.,nendeJ 2 60 -ciio-i, and Narc.-@2)tlcs ot' the z-. Addl National Researc.1, C:@@-,unc.11. @,.'hen such drugs a.,e rdceived, t'sc humor@ of !,he cor,,;-O-,UnA" wt-, I c hI n c I us -iz1 -I ao a a eff@icts o1.-i blood pr,-,ssure., respiratory r,,inute volume., -,.-rapcrature, pupillary si.-e, etc.., Is carrleo' oulo@, A,@i@ter f.@is is ccm-@leted, .the cffects of flic drug on the behavior of fcrrrcr rorptilne addicts '-Pi J,@ti LIDOJpAq I: I 0 U.,l EL. I A q 4 A ti "l@N4ejA4n2q oul uir, I Ati 4 ?,U: I p -17-1 Auzltldf '3-7"6 7p ,)IC> J I C' A I A i D L! I t@: ",I tt I-- 2- 7,,,. 'F -u T -D Li 4( q 4 D I Aq 4 u -p ii J 0 L..' 0 .1 C -1p 'I p D,-ZpnlDul CE61 t pup'IS61 Alnr I UZDTt47,q PDIPnlls *@S.-iip 'Z q.L 0 pug 4'SqP -v'O 4U.Dw'dO!DAPin- JO, A214if.n.jqp UrAPJ-P441/A ZJP $BNJP ' A I IDUI,) 'ODuv-IDIC-f 10 4UZWI-dOfaAZP ZLI4 zl-renti?..A.-- PU2 4DZIIZP 04 4AO PDIJJQD DJP 9 Spoliod U01401PPP 044 BUIJNC- -sAPp 08f:04 C)C,uzzr.4zq Sulouoi bu-jl4 JO SOOIJZEJ JDAO I SJzz4unlOA .401PPL3 J,-_@Lujoj 2 04 SASOP bu[PUD:)Se JO U014PJ4slult@,PP 344 TZAICAUI I q .1 D I u 4:)O 4. tf 0 1 -L -o I @O F * 4 :) Z ' I P 1; 4 4 "lq P r- 4 9 2 'Z J. 4 4 -Ilqpi!PAEI Si SAJO 6 U I S I Llloid A r, 1 o z d i, 3 u,:, v @- u, -ozulzpod '3nip piepup4s z44 t.144,m J PdwOz JOI szolpul Div u 0 1 c s a id d n s i o I a I I D i i o ZDJBDP 244 PuP toDuoul4tqp scaiddns jo DA2118J 04 PzlJlnbaJ afOP 2 ZU4 '34uawljodxz 4ong Ul -A4111qfll uol4@" IPPO DAP4 04 POSPnf Si 41 2)Duaul4sq,,, szosaiddns jo SDAaIIZJ-iBntp aq4 -Ji -oul qdjotu 04 Pi)4DIPPP @,13UOJ4$ s4u3l4t)d,,jl p.-41pn4t 4xzu si aulqdjow wojj 4sqc? 10 stLio4dt:,At 10 22uPJ2vzc!dv 344 4uzAajd 04 Puv DADI I BJ 04 BnJr- zq4 40 A4!llqp 341 4-A41fiq'Pil U014.o!P'PP 2)ACY 04 Alzlll sl 41 C-Dulapoo jo zulqdjo2w JZ41P ub3i 4P44 Buliqw'OSDJ Jof.%Dqzq C2;Dn-ul SnJ,l a44 11 $4ubL'JlJvdxD VDISO I 100'PwJv4d D44 Ut 0 P8'111?490 $41ntzJ uo paseq s4unowe ul ENJP at,'4 24PAIPAD SJV Sul.j24slulu;pp Aq p The fc:llc,,aing. drugs are fovid to he--.I:c either tso hi6,,i taxici@v ar,too @re,-t a -.41::i Ion I tc@,bt I 131-V io be c,-@ntldered as possible subsftfufcs for cod-.Inc-: L Dromoran, I 3-2r-ithyl ether of Dro.-.-,oran, 3-ethyinethylamino-l,-I-(2tdithienyl)-but-i-cne,, and 3-dlethylar,-,Ino- 1-.1 121dithienylli-but-I.Cne. Ti@c following drugs have sufflclcntly low toxicity and sufficiently lov2i addictior liabilities to be regarded as po@tentlal codeine substitutes: d Dromoran'., d 3-;,icfliyl ether of Dromoran, 41, d and I 2:2-dlphenvi-amincethyl vdierate., di-2:2- ylamino butyrate. Of these drugs d lp@.iinv 1-4-m'd in, eth t li e d 3-methyl cther of Dromoran a,-ipcars to be the most pronistng and Is under clid-ical test for a,-itltvssive ve'iue. This, compound Is,, iiowev-@,r' knou-n to be lne@fcc@ive as an anaf2gesic. D Dro,,noran haa been discarded since If,, 13 not an'-cffectivd etntifussi.v-@. It his been recorimended that fc3ting b@- becun wllh d and 1 2 2-CLI;j /. valerafe and viiii di -,2thyl- 2,2-dl,--,henyl-4-diliethylai7tino butyr4t'e. b. P,I-suits Cur,---nl nf7ocrtincr Pet-ic-,d. Durtng thl- first six months of the rzporting pcriod thz -irojccf -gas T@inanced by 2fui,.ds f r o@-.it lo -i @i I 0 f 1) c c it has bezn f"t-,tdnced b-@- 'the T' 't Ice of Ntc-@val 5,'esca.-ch. report- i'nclu-4ic@i results obtaircj duriici both peric2ids of The methods used were i,.41;-. n f I, c I w I t h t hos tr d(@, s c 6- I b4. d.ao v,-- -el 2 0 0 0 :,3 C&I 9A 3 400 :2 -t- < 2 I c@ cr -i, 44 IC) C -i@- m 04 0 -O- n CL 2 11 - M 0 C4 zr 0. is 1< < 2 -i n 0. 0 41 0 40 2 to CL CD a -0 -4. -t- - 0 2 =r zr 10 n 2 n CL (4 :@ll C) w 0 cx CA 0 m 2 tA 0 0 2 iQj 12 N') C'. 0. ('4 CA. f) 0 CL n 2 C4 A 41 0. 0 0 'U ei 0 0 2 CL 0 40 -C n co -1 C 0 a 2 o co . 0 -J Ln n 2 .3 :3 cr 0 4A m 2 lr;F 4A 0 m CL n 9 2 V V - CL 0 -u C =1 Is co co - =r 53 2 0 (L e4 < 0 'O 0 a 03 -1 ta :3 It 2 e4 40 E3 i3. 2 CL 0 in 44 tri n -3 40 0. CL crj 2 0 0 n 0 Z C I co 2 lb 0 0 A 0 E; O - lb 0 C'4 2 0 0 0 n cr cr C C a. (O > 2 a- --t- - - XE =r 03 C (.0 2 0 CL =1 zr CL n cr .0 t% 2 C? m "I 0 0 C: tx rC)_ 0 -11$ 2 7 '$- :fL 64 C 0 el ::J 2 0 CL -2 40 fb (O IN 11 a ea 2 a < x A 2 0 -r Is A 5 Lr e arJ minute volume and In.-4uces behavior stronjiv respiriitor@, rat of scen after.ad.,ninistrition of 15 to 30 me- resem@ling that. morpt-it'ne suffa'tc. The drug Is Irritating to the skin and Is broken do%vn In the body to unknovin sulphur.conta Ining co.-..pcunds which cause-,narked disco.loration of the urine. In som,e patten@s-, peculiar -mental. reactions coti:;Istl2ng either of hypn-a-ogic d-,@-,Iusions or true hallucinations but with mainterai)ce of ltisight v!c@re o.bservedo Th-;A drug Is very effective ln.suppressing abstinence fron, morphine. Dvrimg a pertod of days cxperimentat addiction, part2ial tolerancc-,.@('Ylaz developed. Abs f I i-i c,-% c a wa s p rec I'p t t a f c d y n o r,.-.io r p h I n cEAdo ot, a-brupi' withdrawal., a syndror,ic was ob-orved whi@h r.-sembl-ed abstinence from r,,iorphll,-2 exzept f.-ir t'tme ci-.urt-e; Tiis drug@.was juct@-led to be too t,-)xlc and to have l'oo AlGh addictloo-i liability '@o be consl.4cred a Good .Iurtherrior,-, it was 'retativetv In-zffe,-,t.ive Substitute fdr codelne'.. wh,--n glvcn orally. (4) 3-dl.;-4thv'iarnino I auov;c. i 3 -, r z@ r) -z rc, are a Itiost Td@-n t lc.:-: I those of 1-ind it' Is pot as a prorlisl;,C. subottf@ife fcr 'ib(-r of the f h a do n e series is a v,-rl pos-cni drug. In c!os-@,s of 30 to (@.0m 2 if in-,4Uces .pu.->illary constric@iI@@n, respiratory d--pressioii., .-Slc. -Ti@es-. effl-.cts appear qu'l@te Qrc selill c%,Idz,,it 7@-,' hours ls#Lr5ation oT' the druc. cli-her sul--@-.utancously or orijity. It Is ex frc,-.io. I y ef fect Iv n supore:s;s I iig a bst In-.,nce Trom, norph In -z. The drug to judg--d to bz 4'00 f6KIC and-to h.,ve too tiigh arlclicffon liability fo be re-arded as a prom',.sing -@Lbsftfu.Ic for codeine. 2 ((5) Befa-d-occtyimcthadol. This compound Is sin@llar to (5). Its properties are such that It la not regard--d as a promising substitute for codeine. 17) Dextro. a6d levorotallory il@.,N-diriethyl-3-hydroxy- trorphinan. The dextrcrot2atory form of this con-pou.-Id 'is quite iner-t In man. If does not produce morphine-like elr'fecfs and Is conpletely In,-ffective In reliavlno and supprcs:,irg aLstinen-@-- fro,n morphine* f4o untoward taxit effects uerc observed with do3cs renging at high2@ei 75 ra-1. sub.-.u.-anecusi-,/ or orallv. The levorotatory form of the' druc has.,rnorph:;i,.c-like effects Given In doses of 30 to 60 mg. hypodermically or orally. It is faIrly-effectlvr-- I.-i sup,-,ress?,rg from'morphin2e. The !ev@,-rotatory form is judged to have Gr@-.ater a.;@,'diction liabllif-e than ,-@hat of codeinc. P,-,ji-zver., in the ev@-nt that d -tethyl 0-ro.-7,orin is not found i@-o be a,-; aft'zctive antifussl,.,.z a-ent, r--cc:-mandotl,,.-)n for clinical frial of this a-cnf be -varrantz(-', &,.Ce, judged,by -antf@ial testing., It Is a very effec-'tiv,c- --infitussiv@: dru,-:. (8) ilixiures oz'- N-Aii8,,,In-.rm-)rp,@ire @,.nd r iviixtu es of thes-z drugs hive been studied a' 'he I, n o@ir thz Dru- Addiction f,.iz de-,slc,n,zd to dcfcrr@iing- @ihel-her or no',- the addicition the.more powerful sypthetics can be.aftenuated addition of Nla! I tne., or other without seribusly liipairing therapeutic effects* The following 2r,,iixturei-have been studied-, I to 10 (I mg. Nalline to each 10 mg..norphine)., I to 5 (I mg. N.-III.-.e to -.ach 5 mg. of morphine), and I to 3 (I mg. t4alline to each 3 mg. of morphine)* When administer-ud subcutane2ously, dcvclopment of'r.,or,-.hin,,t-l"rke ou,,)h'aria In former morphine eddlets is blocked with all these mixtures for periods. ranging betwecn .2 to 3 hours. The' higher the proportion of Nalline In the mixture the more eft'ective 2 Is e blocking and the longer It per:lsts. il,il.losts Induced blv-@'m.-,rphlne.13 partily anfagonized bv these mixtures.. Depression of respira'-fory minufe volur-2,1. ho-@.,cver' tz not when the dr2ugs are admin.rstered s:)-ilulta.-ieou-.1y. These przcipita.le abstioen---e or mak@: a-5f.'f in-2nce riore Inliense, rafh,3r tha,,,i.relleve 4t@'* During direct addiction experi2ments,, pofll-.nfs on all t'hre-. mixtures co@-iplained bitterly that the drup did not have th,- desired effects that it had no nkick" and that if dil4i rot m.,,kc i,i er,-, "hish." Desr)ite t'llsi evil2licncc of into--Ifc,:'I-Ion was obseb-ved c x c c s 5 ilv c s om n o I a ii c c., e t A t c r a f c @.,i d y s o f c,@ r -o n I a 1 r, I s - trai4ion of the nix'rur2z r or,] s - $,v., c a t 1:-. c v I d c c c u r -.3 f'f c r i@ c I-,ilection. Thls would perslst for 0-0 r@Ttru@f!-&, an I,,., ta reappz4r follo@vln$j7 t!ic inlectiot. cn s a z o o 7. I r, i,: rl of welrd dreams's cn a br up t vi I f hd r a v@,a 1 o f t h c m I.-. t ur s p a f e n s 7 7-3 experienced wolrd a,-ns-.,dnd hal I,ucit-tation2@ during the f lrs,t 24 hours of abstincnce; thcrcaffar mild riorphlnc-:Ilkc abstinence was observed. The Intensity of rbstinence after withdrawal of the mixtures was less than following withdrawal of morphlnz. Experiments wlih these mixtures have becn encovraglng. They appear to be relatively safe and they could not be abused bv dru@j- 2 addlet3 so their addlc-,ti6n ltabillf,,, lz judged to be low or non-cxistcnt. However, certain drawbacks are ap .parents both morphln%-, and N2alline ere relative-ly Ineffective when ad-nintatcr.-,J ora IV,. It is also unknoan whether eff,-.,.-ts obscrved durino chronic ad.,itnistrat-ion of l.ar-c "addictinc-,' d,-::c-. sou2ld occur if the doses-were In li c, us tia I +he rapeuk I c ra this occurs the could not be vsed clinically. (9) 4-4-Dio,@enyt-,-:--Dim@ethylanino-H,-,--anone-3. This 2 me.-,.ber of ;cries Induces nlid morp@.ine-like affect's when &di-ninis$4ere%-Jl ,in doses of 6-0 mc. either h y,..) o d c r -,I a r orally, t4o serious toxic effects have been 2 observed with tnese [or-,e Only tra.nz 1,znf, s I It-.ht r-zl lzf f --, 'z s z n s @7L-s c r ve-,' f o I I ovi i r, 9 a d,,,,i I n Is t r a f 1) 0 n 0 6(y to '7 M2Cj-. Ca to Pat le;,fs t.-Ii ,h s-.vere sy-npto.-,is of -ifthdr;iv,,21 fr:@.n Ev.:Iu@-tion of dru- Is but at th-- it is r-,card'-d as 4 possibly very po-onising fr,:).m the poinf4 of vi@,.w of lov addiction llzl--Ili (10) d;, 1-methyl-4-pheayl-.'-carbothox-y-azocyclo@@eptane. This compound i's a membe r of the demdrol series. Doscs ranging .up to 150 mg. subcutancous!y induced,neither subjective ror detect- able objective effec-ts in nonfolarant forrhzr morphine addicts. 2Ho vie vc r., wkic npa t I c.-i t s' wh o wer c c t ro n g I v add i c t ed t o mo rp n c received 150 m(;. of the drug In a suppressive exoerlrr-ent serious toxic reactions, dizziness, blurring of vision,, anxiety, elevated blood pre:zure and, In one patient, :Tg2ns of pulmonary edema ensued. "aork with the coinpound has been suspended pending further animal tcxlco,IOGY at the I.?'niversity 07, P-li ch I gan PLAN'S F-12 FUTUni: Immedle'le. During t,he co-ming zlx r@ionlihs we hcpe to complall2@-:1 work on the drugs listed under Items 171:fhroljoh (IOY -above. In add It ion$ ve PI an 'o l@vzsttc@afe -the pr-.,pcr t Its of f,@c fo I low iig morphine I) t4-Allyinordlecetyli-,orphine, (2) N-Propyi-- dihydronormor2phint (3) dextrL-rotato-r,,, t4.A,i lvlnordr"..oran (4) levo- rotatory N-Allylrordromoran, levorotatory of N-Allyinor@.4romora.i. It Is hoped thof s-.Me of these antaconisfs --II I be et'fzci lvr; or@2-it 1-@. in t h c -z v e n el f,i a "F s v c h a.,i a .i tn I ; t Is found, flie effecte ol- oral ad-..Inisfration oy' tlic an'.-ac--nis,' v-4.@en cotblnad wi@h riethadonel, Dromaran and I eti@ier of Dro@-oran -,-III be .tt:.,Jied In the hope of developtno ea 1-@rativ eff-.ctlv,- c@Ir' an ani',.:.Sinist (preferably 'o with a -otent syn.thetic and orally e.IfectlYL- arcl,_zesic drug. !)uc!i riixture3 sh0c.-uld like nlxtures of r-@orphine and Nalline tiov-@ 71 reduced 4ddtction liability. We tilso o ia-I to open a. ne-f- aPL;ar*-cl; t6 t hc roblein and to c f c b I n t r. C,7 2 p n v iz s a t C code I n;L w I t-h a r,.e f a bo I i c --, I cc k t,@i t 4-d I C t h@'/ I ari I noe t hy I propylac6fate. This compound I s r-,po r t c cl t o I nc r ei s c t h -- In tc n@.s I of efr-ect and the len th of action o; o nurber of onalc;c;lc dru-Cis. Combining It with codeine would.represent one way of.increasing t.he @,,up'Ply of cod4ing. Pla-.r.. Wg in4tend to continue the search for an. ati@-quate substitute for codeine until a drug is found which Is judg,cd bv the Drv,,-, Ad--"ictloi Co..,I2nittee c-i- th@- t I o c s c a r c,% Council to fulfil-I all the.n@r--csrar@e c c.. t. 4t. r, ri ici t Cn I 5 L# .0 n s 1 @^-T' 1-he %'4ue.to lark 2 o@' wor'-- to prior to tho, attaln,,Icnf or- thi-s' oil u.- i.-i 9 c u r c,-, rv-.t,locting ptriodi i. lsb;t@lll2$ HO, Fr.-3ser, H*Fo, ant', @VTLI.--rjp A.: AjJdlcfion Liablliil of L'-Ithienylbutylt-ilnes. L9,z 333 (.f-Aar.) 2. Isbr@.11, H., ciid Fr2ascr., -A@ztio,-.s a-,id Addictio,@i Li;abl'tif-o-Zl* of a C t ,',D 7 3 0 i A 1 9 s -b z I F.: I s a n i An2',J I'c t i o,,) L i 1 4' T',-. c r a o I 4 1 4'f-4Cl 4. Fra-Icr i D. zin,! s @-t (,'se of P-;i;-,)flc in E v. .1 I z s 7 I In @.)ress- Direct-.r o'-c'