Synthesis and binding of 6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine and related ring-opened analogs at central nicotinic receptors

6,7,8,9-Tetrahydro-5H-pyrido[3,4-d]azepine (5a) and its N-7-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 Angstrom) that may be less than optimal, we designed compound 5a due to its similar shape but longer internitrogen distance (5.5 Angstrom). Compound 5a (K-i = 45 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. (C) Elsevier, Paris.