临床药理学与生物药剂学

抽象的

Propranolol and Structurally Novel Derivatives as Positive Allosteric Modulators of the Alpha-7-nicotinic Acetylcholine Receptor

Aaron McMurtray, Erin Saito, Shannon Tsang, Anna Lee and Sean Ekins

Purpose: Alpha-7-nicotinic acetylcholine receptor (α7-nAChR) positive allosteric modulators (PAMs) are a potential disease modifying treatment for Alzheimer’s disease, as exemplified by the approved drug galantamine. However, clinical development of this class of compounds has stalled due to poor efficacy and severe adverse reactions, likely related to receptor overstimulation-induced neurotoxicity. In this study, we searched for alternative α7-nAChR PAMs and tested their effect at the receptor.

Methods: A α7-nAChR PAM pharmacophore model was used to screen over 1000 FDA approved drugs and commercially available compounds. Patch clamping was used to assess the six most promising compounds selected from 160 hits. We designed structurally novel derivatives of one of these hits, namely propranolol, and five were synthesized and tested.

Results: Three compounds from the initial virtual screen demonstrated α7-nAChR PAM activity: riboflavin, bromocriptine, and propranolol. Propranolol was noted to possess both α7-nAChR PAM and inhibitory activity at lower and higher concentrations, respectively. Four of propranolol’s analogs also displayed α7-nAChR PAM activity with evidence of functional inhibition at higher concentrations.

Conclusions: Novel compounds with α7-nAChR PAM activity were successfully identified using a computational approach. Several compounds displayed functional inhibition at higher concentrations, which may allow for clinical use without risking overstimulation induced excitotoxicity.