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

Background and purpose: The α7 nicotinic acetylcholine receptor (nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described α7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel α7-selective agonist and characterizes analogues developed from this lead. Experimental approach: Activity and selectivity were determined from rat brain α7 and α4β2 nAChR binding, recombinant nAChR activation, and native α7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells. Key results: Tilorone bound α7 nAChR (IC50 110 nM) with high selectivity relative to α4β2 (IC50 70 000 nM), activated human α7 nAChR with an EC50 value of 2.5 μM and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human α3β4 or α4β2 nAChRs. However, the rat α7 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 (α7 IC50 11 nM, α4β2 IC50>30 000 nM) and activity at both human and rat α7 nAChR (EC50s 1.4 and 2.2 μM and apparent efficacies 61 and 63%, respectively). These compounds also activated native α7 nAChR, stimulating ERK1/2 phosphorylation in PC12 cells. Conclusions and implications: Tilorone, known as an interferon inducer, is a selective α7 nAChR agonist, suggesting utility of the fluorenone pharmacophore for the development of α7 nAChR selective agonists. Whether α7 stimulation mediates interferon induction, or whether interferon induction may influence the potential anti-inflammatory properties of α7 nAChR agonists remains to be elucidated. British Journal of Pharmacology (2008) 153, 1054–1061; doi:10.1038/sj.bjp.0707649; published online 24 December 2007