Activation of a7-nicotinic acetylcholine receptor (nAChRs) has broad therapeutic potential for the treatment of cognitive deficits associated with schizophrenia, Alzheimer's disease, Parkinson's disease, and attention-deficit/hyperactivity disorders as well as inflammation and neuropathic pain. Although activation of a7 nAChR ion channels is primarily controlled by the binding of ligands at conventional orthosteric site, it is also regulated in either positive or negative ways by binding of ligands to an allosteric site in the transmembrane domains which is topographically distinct from orthosteric site. Among the Type II Positive Allosteric Modulators (PAMs) of a7 nAChRs, 4BP-TQS (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) is unique in a sense that in addition to being a potent PAM, it also behaves as an allosteric agonist. In this work, we have developed an expeditious microwave-assisted synthesis of 4BP-TQS, performed separation of its enantiomers by chiral HPLC followed by their biochemical evaluations. Initial electrophysiological characterization in Xenopus oocytes revealed that the biological activity almost exclusively resided in the (+)-enantiomer 1b  (GAT107). The (-)-enantiomer 1a  had negligible activity as an allosteric agonist or PAM and it did not affect ago-PAM activity of (+)-enantiomer 1b  , when applied together. X-ray crystallography studies revealed the absolute stereochemistry of the active enantiomer 1b  to be 3aR, 4S, 9bS. This enantiomer represents the most potent ago-PAM of a7 nAChRs and is considered as a candidate for further evaluation in vivo.

Stereochemical requirements within the tetrahydroquinoline scaffold for the positive allosteric modulation at alpha7 nicotinic acetylcholine receptors

246th National Meeting (2013)

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