PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor.

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.

• Authors: Lisa M Broad, Catherine Felthouse, Ruud Zwart, Gordon I McPhie, Kathy H Pearson, Peter J Craig, Louise Wallace, Richard J Broadmore, John R Boot, Martine Keenan, S Richard Baker, Emanuele Sher
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 452 Issue 2 Pg. 137-44 (Oct 04 2002) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12354563 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 5'-phenylspiro(1-azabicyclo(2.2.2.))octane-3,2'-(3'H)furo(2,3-b)pyridine
• Bridged Bicyclo Compounds, Heterocyclic
• Chrna7 protein, human
• Chrna7 protein, mouse
• Nicotinic Agonists
• Pyridines
• Receptors, Nicotinic
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• Serotonin Receptor Agonists
• alpha7 Nicotinic Acetylcholine Receptor

Topics

• Animals
• Bridged Bicyclo Compounds, Heterocyclic (metabolism)
• Dose-Response Relationship, Drug
• Female
• Humans
• Mice
• Nicotinic Agonists (metabolism, pharmacology)
• Oocytes (metabolism)
• Pyridines (metabolism)
• Receptors, Nicotinic (physiology)
• Receptors, Serotonin (physiology)
• Receptors, Serotonin, 5-HT3
• Serotonin Receptor Agonists (metabolism, pharmacology)
• Tumor Cells, Cultured
• Xenopus
• alpha7 Nicotinic Acetylcholine Receptor