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• t , PRI~AIIATZOH ~ FROPIW~Lq OF NICOTIIiIE ANLLOG~S ,aer XZT.. lt~Oll~ NO. RD.2673 RES2'ILT.C'L'Z;D zo.6.19y9 &UTItOR: K.D. I~L lburn :l:fi~:/llD, !~: C.1. £yres PRO(;. lug. : 12.07.05 D ZSTLTBIr£ZOH: i i Dr. S.J. Green Dr. I.M. Jlu8he, Dr. 1.A. Sm~oz~l I.M. O£bb, Koq. R.S. Made, hq. I.G. ll:teholl8, lr~q. Bert g. ~Letermhaun Dr. F. fJeebo~er Hr. &.3. r~ruesT~sk~ Dr. C.J.P. de $Lqu4Lr8 Dr. D.G. Foltma L£brary ColRr Ho. 1- " " 3, 4 lie M 5 " " 6, 7, 8 " " 9, 10 " " 11 " " 12 " " 13 " " 14 " " 15 n n ].6, 1-7 CQ~ NO.t ~,~ r Co LTD - MINNESOTA TOBACCO LITIGATION

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s:o~/sec Group ~search & Development Centre. Brlr~Lsh-Amsrica• Tobacco Co. Ltd., S0D~t~N. 20th June, 1979 PIU~A/AZZOII ~ I~OF/D~IX8 OF ]IZCOZZllE LIULLOG;JT~ - ?AILT ZZZ (Keport lio. IC0.Z673 RestrLcted) f I Che~Lcal compounds related to ~cotlne hate been 8tudled i• an attaapt to throw l£sht ou tbm molecular c~ar&cterlot~c8 needed to product a ~cottne-like ef£ect, albeit in the restricts4 sense of the effect on muscle tissue. The 1turk described was carried out under co•tract at the Cheaical ~£ence btablishaent, Portou Dots, W£1tshire. PoXZovin6 the ~L~catlous £:om earlier stmL~es, effort was centred ou the synthesis o£ s particular analogue. The e~fort was unsuccessful, but other a~alosue8 obtalned ~ the course of th~s prostate here been evaZuated phermacoZol|£Ca/ly. The resuZts are consistent vLth, but do ~ot prate, s shape hypotbos~s for • n~cot/ne ulolue to •ct as an e£fectLve sutnic for ~cotine itself. A net k£nd o£ nicot£ne analosue Ls proposed on the beats o£ the hypothes/e. ~t Ls proposed that the new analoSue be 8yntheeLead and tested, sad that two =o~pouzd8 stud£od £n the preeemt report (no~cotiaa sad a trlc~:llc azmlosus) shollld be e:mm~ed 4n • tr~dm: rm~e o~ phatmsco~os~cal tests. ~mum~ '~,~ - Co LTD - MINNESOTA TOBACCO LITIGATION

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-2- • o- Z~ODUCT ION The present z~pott contLnues 8 series (1, 2, 3) chat £s concerned vith the relst£amsh4p betveen cbamLcal structure and phstmscoloK£cal actLon of compounds closely related to the nicotine molecule. The approach is based on the idea that constraints on the Keometry of the u~cotium molecule may help to ahoy the essential featmce• of the bloloK~81 receptors for z~cotine. It va• vlth the :eKtet of both patt£e• that the verb of Dr. J. J~daeleT at tha London School o£ Phazznc7 had to be cu:ta£1ed prematurely (3). However, the CharLes1 Def~nce E•ta~lLehmemt at Porton a6reed to eonttnu~ tho work, and Dr. ~LLdseley active17 as•Lsted the transfer. Work cat,ted out at Porton bet3meu Janua:7 1977 and Januax7 1979 i• dLscussed iu thls report. Cop£e• of the reports from Forton ere included 8• AppeQdice• Z :o VI, sum y£lUre 1 shay• the •tr~cture and ulsber~ of ~m~ound• dl • cue sod. DZSCUSSXON (i) SFnthet£c $cudLes The nicotine molecule can be dravn on paper Ln ave con~oz~stion:, [ and ZZ: I Earlier wock (1, 2) had sboun that ZZZ had ~tttle snCqoniJtic e~ftct towards nieottns, mhmreas lV Ins an ef£ect£ve antaso~Lsc4c. Zt ~e pressed that [V competed more affe~t£vely for h re~.aptor sites. m C~ ~r~ '~,'~ " Co LTD - MINNESOTA TOBACCO LITIGATION

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-3- E Consaqmmtly aeeempes were made to synehes£ze V, initially by conzraet wizh Dr. Nidseley (3). E Forton couctnued the synthesis and overcame ~he probZeRs encountered by Dr. Kidgeley. They produced a eompoLmd VX whLeh it was hoped would undergo rt~8 closure to pz~duce V. On~ors:must41y, z-LnS elosuxe yes no: achieved. An sL~trnaz£ve synthesis wu usshnd, but r~ais too felled. The experhnntal work is described m r~ 0% ~,~ ~ Co LTD - MINNESOTA TOBACCO LITIGATION