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u i Experimentation in the pharmacologic, psychopharmacologic, and physiologic effects of nicotine (1) continues at an extraordinarily high level. . Within the last year,.a stereospecific binding site for nicotine in rat brain membranes relationships (SAR) have been established and no SAR that encompass both - . r. . :. central and peripheral nicotinic systems has been proposed. Efforts to establish such relationships would be facilitated by the availability of 'additional wti,i' ~'~"W analogues possessing the nicotine ring geometry.[ Some time ago, Hagl~.k reported =i ~ that 4-methylnicotine (4) was devoid of'nicotinic cho'linergi.c/activity,.and ~ M!F ;suggested that the pyridine methyl group of 4, which is ortho.to its A-methyl-r~; : . ' .. ~ X :. PY rrolidine .ringr interferes with the ring-ring conformation required at the " ~ • ... .] R~Y , •.r . . ../' . ,10 . . . . . . nicotinic receptor.~5-8 We now report results which suggest that methyl s . ... - `' ~..;I. 4 , •/.~• . '. . ' . . . - .. . . .. : ~sJ substitution on.the nicotine molecule acts not by limiting the availability of ~ .~. t ....;. :, ~~ .. .. ... ' ...~ . .. ,.. . . - _ S`•F' .~y.. ..:: S7 , . ._.. - A N. important conformations (Haglid's postulate ) but by reducing accessibilit- ~ ." X~~,'~"~ t© the pyrrolidine nitrogen By employing chemical reactions as models for t4)wth~(V .;r. biological interactions, we have observed novel steric effects in these° ' . . . : . - - - . ~ conformationally mobile systems which can be correlated with the pharmacologic~~ •' ` activitiesobserved. -..The nicotinoids included in this series demonstrate a+ . . . .. .. , , . S..k rl wide range of activity for, the tests examined and can serve ase the basis fo': more detailed structure-activity relationships in the future.

have a .LU 5a ana active than tions can be made: pyrrolidine -.: tests; , (2) pyridine -on inspection of and maxima for each compound as nicotine. The calculated barriers are large. additional nicotine in (1) a SAR which , loss would 0 (3) able=lists the would 0 r a; pinpoint specific critical structural .... . ' . . . s«:::_-.c: . : r:.~. ..... features, such as steric hindrance/at both nitrogens and molecular conformati.on The pharmacological test results for these nicotinoids are detailed in Table 10 Placement of a .. : ~6 substantial effect, 6 methylnicotine b ing 3-7 times A guinea pig ileuro tests and 2 methylnicotine being : -l Ckf these same two tests. A number of substitution of a pyridine single: methylp group on the nicotine nucleus can cle , cis-3'-methyl- and trans-3'-methylnicotine are though both are less active.than nicotine; activity; (4), substitution close the nitrogen increases activity in one case . . . , ti;;. another; and (5) substitution^ distant from the pyrrolidine ring (at CS and . `ti; _ ~ . . ~ Cs).has only a modest effect on activity, increasing activity in the case of :.` _ -~ ~es- ~~ : , . 6-methylnicotinen ln order to evaluate Haglid's postulates-7 of conformational control of activity as stated above, we included in our studya a number of , . ... . .: . .. .. _ ~ < ~ . ,: .. . . .,.: . .... .. ,. . , - . ,, . • ., ~.. ..-c _ , . .~-,,, - . . ..~ .~. ~. ., ~ .' .. : compounds which we considered to have specific conformational features based : . ,, .,. iding models. in this field, we carefully designed9 a series barriers but probably would not change the trend seen for this molecular reported as we place more emphasis calculated, an:d it is on the relative order observed than on the actual values important to note that unrealistically high barriers are often the-results of 14 such procedures. The important structural conclusions from these calculations

include: (a) 4-methylnicotine5-8- (4) and 2-methylnicotin -8,15 Mv botkAIOfi qbAlvtL have a methyl group ortho to the pyrrolidine ririg and have similar pyridine-pyrrolidine conformational profiles; (b) cis -3 " -methylnicotine (21-D C2i4-H:C3"-CH3 cross ring interaction which is analogous to the C-CH3:C3'-H.interaction in 2 and 4; (c) the C3,-or C5,-methyl group of trans- and cis-5'-methylnicotine (5c) respe ctively ;F ~ affect pyrrolidine ring interactions without modifying ring-ring energetics; and (d) the pyridine methyl group.of 5-methyl- and 6-methylnicotine (5 and 6 have no effect on either ring-ring conformations or pyrrolidine ring conforma- To.,quantify.the intramalecular interactions- arising in these nicotinoids substantiate `the- conformational analyses based on Dreiding models

> :'nicotine is unlikely to be due to steric congestion at the pyridine nitrogen °.= ... ~ _ ... . . . . . .... . . ' . , . ' - , . , j , since significant activity is found for 6-methylnicotine. A particularly `, be_ destabilized in N---N" anti conformations. The low activity of 2-methyl- nitrogen for suggest that activity, and sibility. rates of alkylation these analogues was chosen as a ; tion o In order , i r.. striking structural feature of the least active analogues their PY • . .. ,.. . ,. ridine methyI groups produce severe steric hindrance large sectors •of'their 'possible 'conformations. pyrrolidineA nitrogen accessibility that the pyridine'methyl groups a<-; in 2 and 4 decrease±~that a ces - ' is crucial (2 and 4) at 5 t ~Y. i:~;!i'!yw4 k a

This large rate retardation is particularly novel in of rapid ring-ring rotation about the C_ft7_C2i__pivot bond to favor conformations µ significant steric effect and 4), it is reasonable that ather .,. in which there. is minimum

}' C. Ramano and A Goldstein,Science,'210, 647-650 (1980). L. G. ~Abood, K. :7 Lowy, A..' Tometsko, M. MacNeil, Arch."I Ther. 237', 213-227 (1979) : ' L. T. Meltzer, .T 'A. Rosecrans, macology, 68,-283-286 (1980).• . Haglid, Acta Chem. Scand:," 2~,1, 329-334 (1967). ' F. Haglid,Acta Phar~ Sue~ica: ,: 4, `117-138 (1967) . - F. Haglid in "Tobac A1 loids and Related Compounds", U S k on E}Iler,; , ~ 'Ed. , Macmillan,` New York, 1965, pp.` 315-319 E._ -Leete and -S. ' A ', S.: Leete, `J: Org. Chem. , ' 43, 212'2-222'S (1978) ': ' Note, . ; in particular,'the pharmacology discussion in~the experimental section of ~this paper. ~ , , yt 1 `' Si~.i...: ~y '•~~•.r "t~f.~:,f f ~1 .... ,~,~ ~. ,. • . . ••- . ..-. ..• ,. • . . . . _ .. :;'• . .. ~ _-•.. . . . . -.;Full details, of the synthesis 'of the new compounds reported herein will _ =:be.described elsewhere.'_`Satisfactory elemental and spectroscopic.analyses F~,were obtained for all.-compounds .'' Unless otherwise indicated,,,all com- `:; :pounds=.are racemic mixtures ;A11 pharmacological -tests'reported herein were conducted under contract outside of Philip Morris r 15." Sarµ~~r p~~ The various .pharmacological tests reported"herein represent;:the tradi ~1 -tional `:ones =used '-for. 'screening nicotinic cholinergicc agents ~'.It is rec= , a . . , ognized.:<°that: 'mang different . sites of action -`as well as ' niechanisms . of ~ r:... . ,ry .. .._ . :. . .. .. . ,.. _ action : a,re clearly ; involved ,~•:; We :`are ` particularly interested :.;In the activity trends observed rather than the operative detailed pharmacolog , fi ical mechanisms ~;, , ~, ,?~ ~1 ` ~5 f ft ~ ~, t.+ n'": r.ir~' , As a baseline geometry for the calculations, a=partialZy optimized ni'KVrr~x };:otine•. coordinate system-was usedX. The nicotine. coordinates evolved from i,r7, . i .~ fully optimizing pyridine and N-methY1PYrrolidine 'structures seParatel , Y,z -adbtli theetithfr`th fll y n.susequeny usngse gomeres .ogeter-oeu_ nicotine - ... .' . . calculations. :;;The nicotine structural parameters-;,varied `''for energy, ~ minization included the,inter-ring distance, the side-to-side-and up-and- 11 down torsions of the pyridine ring, the methyl out-of-plane and side-to- side motions, and the H(2) and H(4) in-plane angles.. At fixed values of , the inter-ring torsion angle, seven internal structural:!parameters were varied independently until the energy minimum was found 5'':.The seven ~' parameters chosen.exhibited the greatest coulombic forces in the molecule..`Y This procedure was repeated at 10° increments of t-'•;'These nicotine :geometries were used for the INDO studies of the methylnicotine conforma-,, tions by substituting -CH3 coordinates in place of the appropriate -H -, coordinates."- For each compound, thel2ethyl rotational angles were optimized ,,; ~ ..ts, For compaB'son, an INDO 'calculation was. also run on the. reported x-ray ~: s**_ucture . of nicotine using standard hydrogen parameters; ` the molecutar :energy, we calculated from these x ray data greatly exceeded our.results N ~z. 4 ' `~ ~000128509~d; ~~ „sca>a ~~,_ dr,5,~~: x~'cMr~

t 12. 1 1 I 1 1 18 on the partially optimized nicotine geometry at all values of t•7 Full idetails of these calculations will be reported elsewhere by one of us (R. W. Dwyer). N---N' refers to the relative orientation'of the pyridine and pyrrolidine nitrogen atoms. 3831-3842 (1973). R. J. Radna, D. L. Beveridge, and A. L. Bender, , C. H. Koo and H. S. Kim, Daehan Kwahak Kwoejee, 9, 134-141 (1965)~; Chem.~' .Abstr., 65, 6431e. . .. K. Ahmed, in "Advances in Chemistry:Computer-Assisted Drug Design", R. E. Christoffersen and E. C. Olson, Eds.•, American Chemical Society, Washington, • . . . < D.C., 1979, Chapter 12. ~:. ~ . .. . _ . . . . , ,'r~. See, for example, D. S. Fullerton, K. Yoshioka, D. C. Rohrer, A. H. L. From, and K.' Ahmed, Science, 205, 917-919' (1979); Mol. Pharmacology, 17, 43-51 (1980); D. C. Rohrer, D. S. Fullerton, K. Yoshioka, A. H. L. From, . .. .. .... . - ~ - . . ~ . . . :M~;n J. Am. Chem. Soc., .-. ` • . . . . - . ..... . E. B. Sanders, H. V.. Secor, and J. I. Seeman, J. Org. Chem., 43, 324-330 :.(1978)•, J. Org. Chem., 41, 2658-2659 (1976)~. . M. Cushman and N•. Castagnoli, Jr., J. Org. Chem.,`37,' 1268-1271 (1972) : . M. L. Rueppel and H. Rapoport, J. Am. Chem. Soc., 92, 5528-5531 (1970).' - ~ e - f ~V.. ' i .... ~ ~.t v'.. . . . . . .. . . .,. .. ,t.r .r . '~r . . . . . `....j"~! . . . i, .: ._ .. ., • ' .. J. McKenna, Topics in Stereochemistry, 5,I275-308 (1970). see W. T. Wipke and P Gund, J.-Am. Chem.. Soc., 98, 8109'-8118 (1976). ' For an elegant discussion on conformationally dependent congestion factors, ~ A.: T.. Bottini in "Selective Organic Transformations,"n Vol. '1, 4 an alkylating reagent. These invertomers may also be able to complex with biological systems with different kinetic parameters. See also ref. :Lett., .1901-1904 (1978) Nicotine alkylation is complicated by the presence of two stereoisomers each of which is capable of reacting with .18 and J.- I. Seeman; H. ' V. Secor, H. Hartung, and R. Galzerano, J. Am." Chem. Soc., 102, 7741-7747 (1980) 23. M. Mattila and A. Vartiainen,. Acta P'harmacol. Toxicol., (1962)'• +. 19, 330-336 Thyagarajan, Ed., Wiley-Interscience, New York, N.Y., 1970, pp: 89-142.• ` `.~ ; . rt H~ C Brown and A. Cahn, J. Am. Chem. Soc., 77, 1715-1723 (1955) J. I. Seeman, H. V. Secor, J F: Whidby; and R.'L. Bassfield, Tetrahedron c B. S. A. Melikian, Ph.D. Thesis, University of California, San Francisco, CA, 1973; . University Microfilms No. 73-29,927; Chem. Abstr., 80, 82560w. t 25. The lower activity of 3,~'e and Vt may also be related to de.creased pyrrolidine accessibility demonstrated in preliminary iodomethylation studies on these compounds (J. .L. Seeman and H. V. Secor, unpublished 'results). Torsional motion about the C2,-Cg, and C3,-C4, bonds can be a major source of relief of steric strain for these compounds. 9000128510 ~ 'j: F' gt4•,. f_ %N r s~,;~ x r- K..;~;f'. ..L" _ ',:Fti~.,:~:; . N! Y : +; /t (.~b s '~"~ rr t(~ r K 1 ~M;,V•I ~"~ .'~...

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6 ~ 13(3.1) 1.5 z 0 U Z 0 F- W > 1.0 a J W ~ ~ ~ u a 0.5 ... ~ c 0 ~ 1-- zt-%zloooo LD50 GUINEA PIG ILEUM RAT BLOOD PRESSURE 5 6 N N PYRROL_IDINE NITROGEN ACCESSl6IL_ITY(fNI)