α7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues

Background and purpose: The alpha 7 nicotinic acetylcholine receptor ( nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described alpha 7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel alpha 7-selective agonist and characterizes analogues developed from this lead. Experimental approach: Activity and selectivity were determined from rat brain alpha 7 and alpha 4 beta 2 nAChR binding, recombinant nAChR activation, and native alpha 7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells. Key results: Tilorone bound alpha 7 nAChR (IC50 110 nM) with high selectivity relative to alpha 4 beta 2 ( IC50 70 000 nM), activated human alpha 7 nAChR with an EC50 value of 2.5 mu M and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human alpha 3 beta 4 or alpha 4 beta 2 nAChRs. However, the rat alpha 7 nAChR maximal response was only 34%. Lead optimization led to 2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-xanthen-9-one(A-844606) with improved binding (alpha 7 IC50 11 nM, alpha 4 beta 2 IC50 > 30000 nM) and activity at both human and rat alpha 7 nAChR (EC(50)s 1.4 and 2.2 mu M and apparent efficacies 61 and 63%, respectively). These compounds also activated native alpha 7 nAChR, stimulating ERK1/2 phosphorylation in PC12 cells. Conclusions and implications: Tilorone, known as an interferon inducer, is a selective alpha 7 nAChR agonist, suggesting utility of the fluorenone pharmacophore for the development of alpha 7 nAChR selective agonists. Whether alpha 7 stimulation mediates interferon induction, or whether interferon induction may influence the potential anti-inflammatory properties of alpha 7 nAChR agonists remains to be elucidated.