Propranolol and Structurally Novel Derivatives as Positive Allosteric Modulators of the Alpha-7-nicotinic Acetylcholine Receptor | OMICS International| Abstract
ISSN: 2167-065X

Clinical Pharmacology & Biopharmaceutics
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  • Research Article   
  • Clin Pharmacol Biopharm 2020, Vol 9(1): 1
  • DOI: 10.4172/2167-065X.1000192

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

Aaron McMurtray1,2*, Erin Saito1, Shannon Tsang1, Anna Lee3 and Sean Ekins4
1OC Neuroscience, 4000 Barranca Parkway, Irvine, CA, USA
2Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
3Wayne State University School of Medicine, Detroit, MI, USA
4Collaborations Pharmaceuticals, Inc., Raleigh, NC, USA
*Corresponding Author : Aaron McMurtray, OC Neuroscience, 4000 Barranca, Parkway, Irvine, CA, USA, Tel: 1-805-316-5025, Email: [email protected]

Received Date: Feb 10, 2020 / Accepted Date: Feb 25, 2020 / Published Date: Mar 03, 2020


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.

Keywords: Propranolol; Positive allosteric modulator; Alpha-7- nicotinic acetylcholine receptor; Alzheimer’s disease

Citation: McMurtray A, Saito E, Tsang S, Lee A, Ekins S (2020) Propranolol and Structurally Novel Derivatives as Positive Allosteric Modulators of the Alpha-7- nicotinic Acetylcholine Receptor. Clin Pharmacol Biopharm 9: 192. Doi: 10.4172/2167-065X.1000192

Copyright: © 2020 McMurtray A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.