- Synthesis and binding of 6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine and related ring-opened analogs at central nicotinic receptors
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6,7,8,9-Tetrahydro-5H-pyrido[3,4-d]azepine (5a) and its N7-methyl derivative 5b were synthesized and evaluated as potential nicotinic acetylcholinergic receptor (nAChR) ligands. On the basis that 6,7,8,9- tetrahydro-5H-pyrido[3,4-c]azepine (4a), which binds at nAChRs with low affinity (K(i) = 1100 nM), possesses an internitrogen distance (4.6 A) that may be less than optimal, we designed compound 5a due to its similar shape but longer internitrogen distance (5.5 A). Compound 5a (K(i) = 46 nM) was found to bind with enhanced affinity. However, unlike what is seen with nornicotine/nicotine, N-methylation of 5a reduced affinity (5b; K(i) = 268 nM) rather than enhancing it. The results suggest that 5 may interact at nicotine receptors in a manner that is somewhat different from that of nicotine. Ring-opening of the pyrido[3,4-d]azepine ring led to a series of 3- (2-aminoethyl)pyridines 21 that retained the affinity of the cyclic compound. Subsequent modification, including further chain lengthening (e.g. aminopropylpyridines 22) and introduction of unsaturation, ultimately led to the development of a series of 3-(2-aminethoxy)pyridines 27. Simple N- substituted derivatives of 27 were found to bind with K(i) values of 20 to 35 nM. Because parallel structural changes in several series of related compounds did not result in parallel shifts in nAChR affinity, it is unlikely that all the investigated compounds bind in a similar fashion at these receptors. Nevertheless, some of these compounds represent novel classes of nAChR ligands.
- Cheng, Yun-Xing,Dukat, Malgorzata,Dowd, Matthew,Fiedler, Wolfgang,Martin, Billy,Damaj, Mohamed Imad,Glennon, Richard A.
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p. 177 - 190
(2007/10/03)
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- 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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