PSAB-OFP,a selective alpha 7 nicotinic receptor agonist,is also a potent agonist of the 5-HT3 receptor |
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Authors: | Broad Lisa M Felthouse Catherine Zwart Ruud McPhie Gordon I Pearson Kathy H Craig Peter J Wallace Louise Broadmore Richard J Boot John R Keenan Martine Baker S Richard Sher Emanuele |
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Affiliation: | Eli Lilly and Company Limited, Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Surrey, GU20 6PH, Windlesham, UK. broad_lisa@lilly.com |
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Abstract: | 5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 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 alpha 7 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 alpha 7 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 alpha 7 receptor ligands. |
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Keywords: | α7 Nicotinic receptor 5-HT3 receptor Cross-reactivity Spiroazabicyclic |
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