- Pyrrolidine-modified and 6-substituted analogs of nicotine: a structure-affinity investigation
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Because the structural requirements for the binding of nicotine to central nicotine receptors remain largely uninvestigated, we undertook a systematic investigation of pyrrolidine ring-opened analogs.This led to a subsequent investigation of related conformationally restricted derivatives of these analogs.The results are reported relative to the binding of several well-known and widely used nicotine receptor ligands.Although none of the ring-opened analogs binds with higher affinity than (-)-nicotine (Ki = 2.3 nM), 3-(N-methyl-N-ethylaminomethyl)pyridine (12a; Ki = 28 nM) binds with significant affinity.A conformationally restricted analog of 12a, N-methyl naphthyridine 30b (Ki = 18 nM), binds with similar affinity. 6-Substitution of 12a and racemic nicotine seems to be tolerated when the substituent is halogen or methyl.In functional studies (hypolocomotion and antinociception in mice; stimulus generalization in nicotine-trained rats) 30b retains nicotine-like properties.Several of the 6-substituted compounds were 2 to 20 times more potent than (+/-)nicotine.Although the intact pyrrolidine ring of nicotine appears important for optimal affinity, its presence is not an absolute requirement for activity, and 6-position substitution of the pyridine nucleus can influence both binding and functional activity. - Keywords: nicotine; nicotine receptor; drug discrimination; antinociception.
- Dukat, M.,Fiedler, W.,Dumas, D.,Damaj, I.,Martin, B. R.,et al.
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p. 875 - 888
(2007/10/03)
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- Organometallic Methylation of Nicotine and Nicotine N-Oxide. Rection Pathways and Racemization Mechanisms
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The reaction of nicotine with methyllithium leads to 2-methylnicotine as a major product in addition to the previously reported 4- and 6-methylnicotines.The reaction of nicotine N-oxide with methylmagnesium bromide furnishes both 2- and 6-methylnicotine.The product composition of these reactions is strongly dependent on the experimental conditions; the effects of solvent, temperature, and relative reagent concentration are presented.The methyllithium reactions lead to partially racemized methylnicotines, and the recovered nicotine is often nearly optically pure.Independently, (S)-(-)-6-methylnicotine was treated with methyllithium and was recovered with complete retention of optical activity.These results suggest that loss of optical purity in the formation of methylnicotines in these methyllithium reactions occurs during the reaction itself and is not due either to racemization of the starting material or to subsequent racemization of the initially formed product.
- Seeman, Jeffrey I.,Secor, Henry V.,Howe, Charles R.,Chavdarian, Charles G.,Morgan, Larry W.
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p. 4899 - 4904
(2007/10/02)
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- Steric and Conformational Effects in Nicotine Chemistry
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The stereoselectivity of iodomethylation of nicotine and seven nicotine analogues having pyridine alkyl groups was determined by using 13C NMR.Alkylation at the pyridine (N) and at the pyrrolidine (N') nitrogens was observed.Two modes of N'-iodomethylation occur, cis and trans to the pyridine ring.N'-Iodomethylation occurs regioselectively cis to the pyridine ring for all compounds examined.The N/N' and N'cis/N'trans ratios for the nicotinoids were evaluated with regard to (1) the orientation of the N'-methyl group in the free base, (2) conformational properties of the pyridine ring with respect to the pyrrolidine ring, and (3) steric hindrance and buttressing effects on the pyridine nitrogen.The Curtin-Hammett principle and the Winstein-Holness equation are used to analyse reactions.
- Seeman, Jeffrey I.,Secor, Henry V.,Chavdarian, Charles G.,Sanders, Edward B.,Bassfield, Ronald L.,Whidby, Jerry F.
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p. 3040 - 3048
(2007/10/02)
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- THE RADICAL AND ORGANOMETALLIC METHYLATION OF NICOTINE AND NICOTINE N-OXIDE
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2-Methylnicotine is a major product in the reaction nicotine with methyllithium and methyl radical, in addition to the previously reported 4- and 6-methylnicotines.The reaction of nicotine N-oxide with methylmagnesium bromide furnishes both 2- and 6-methylnicotine.
- Secor, Henry V.,Chavdarian, Charles G.,Seeman, Jeffrey I.
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p. 3151 - 3154
(2007/10/02)
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