Exploring the structure activity relationships of halogen containing N-(pyridin-3-yl)- piperazines and homopiperazines at α4β2 nAChRs

Abstract

Introduction: The α4β2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Particular halogen containing compounds have showed promising results at α4β2 subtype of nAChR. Aims: To explore and understand the structure activity relationships of halogen containing α4β2 agonists. Potentially, this could lead to rational design of superagonists. Methods: Consecutive series of halogen containing compounds were investigated by using two-electrode voltage-clamp electrophysiology. Discussion: The results of the tested series of compounds show a tendency in increasing efficacy with the increasing size of the substituent: H< F < Cl < Br; this applies for both the (α4)2(β2)3 and the (α4)3(β2)2 stoichiometries of the α4β2 nAChR subtype. Interestingly, the Br and Cl containing homopiperazines are superagonists at the (α4)3(β2)2 subtype. Activation of the cholinergic pathways elicits antinociceptive effects, which means finding a successful agonist or a superagonist could lead to a new type of analgesic dealing with chronic pain.