Synthesis of H-bonding probes of a7 nAChR agonist selectivity

The a7 subtype of the nicotinic acetylcholine receptor (nAChR) is the target of studies aimed at identifying features that will lead to the development of selective therapeutics. Five arylidine anabaseines, three with pyridine rings and two with the pyrrole rings, were synthesized in 35–65% yield via aldol condensation. The compounds are homologs of benzylidine anabaseine and were chosen for synthesis because they provide either a hydrogen bond acceptor (pyridines) or hydrogen bond donor (pyrroles) that may interact with the receptor within the benzylidine selectivity motif. Initial analysis of the new compounds at 100 lM concentration reveal that the two pyrrole anabaseines are good partial agonists of the a7 nAChR, having 40% of the efficacy of ACh, efficacy comparable to 4OH-GTS-21, and dramatically enhanced efficacy relative to the 2and 4-pyridinyl compounds. The pyrrole compounds were confirmed to be a7 selective, displaying preference for this receptor over muscle and heteromeric neuronal receptor