PSAB-OFP, a selective alpha7 nicotinic receptor agonist, is also a potent agonist of the 5-HT(3) receptor.

摘要

5-Hydroxytryptamine 3 (5-HT(3)) and alpha7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha7 receptor agonists. We used a recently reported selective alpha7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha7 receptor ligands.