Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release Peter A. Crooks, a, * Joshua T. Ayers, a Rui Xu, a Sangeetha P. Sumithran, a Vladimir P. Grinevich, a Lincoln H. Wilkins, a A. Gabriela Deaciuc, a David D. Allen b and Linda P. Dwoskin a a Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA b Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University HSC, Amarillo, TX 79106 USA Accepted 20 October 2003 Abstract—N-n-Alkylation of nicotine converts it from an agonist into an antagonist at neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogues exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood–brain barrier choline transporter. # 2004 Elsevier Ltd. All rights reserved. 1. Introduction Considerable effort has been focused on the develop- ment of neuronal nicotinic receptor (nAChR) agonists as therapeutic agents. 1 6 On the other hand, relatively few studies have focused on the therapeutic develop- ment of nAChR antagonists. Thus, only a few subtype- selective antagonists are currently available for use as pharmacological tools to investigate the physiological roles of specific nAChR subtypes. 7,8 The rationale for the current research is based on the finding that nicotine stimulates all known nAChR sub- types, and that N-quaternization of nicotine converts it from an agonist into an antagonist with enhanced nAChR subtype selectivity. Several classical nAChR antagonists are bis-quaternary ammonium structures. Hexamethonium chloride and decamethonium bromide, both bis-quaternary ammonium salts, are considered simplified analogues of d-tubocurarine. 9,10 The latter drugs have been used to distinguish between peripheral nAChR subtypes, specifically neuromuscular and ganglionic nAChRs. 10 14 More recently, quaternary ammonium N-n-alkyl analogues of nicotine have been reportedtobenAChRsubtype-selectiveantagonists. 15 20 These latter findings prompted the evaluation of a series of quaternary ammonium compounds containing catio- nic azaaromatic head groups for their interaction with a4b2* and a7* nAChRs (asterisks indicate the putative nature of the designation of the native nAChR sub- type 8 ), as well as their interaction with the as yet to be elucidated nAChR subtype mediating nicotine-evoked dopamine release. While it is generally believed that quaternary ammo- nium compounds do not easily access the brain due to their charge and polarity, precedence from the literature shows that such compounds have the ability to access the brain via several mechanisms, including the blood– brain barrier choline transporter. 21 The hypothesis for the current study is that nAChR subtype-selective and brain-bioavailable antagonists will result from modification of the nicotine molecule by (1) quaternization of the pyridine-N atom with a lipophillic substituent to afford N-substituted analogues, and (2) modifying the structure of the nicotinium cationic head group. 2. Chemistry Compounds 1–3 (Fig. 1) were prepared by reacting S- ()-nicotine with the appropriate n-alkyl iodide in 0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2003.10.074 Bioorganic & Medicinal Chemistry Letters 14 (2004) 1869–1874 *Corresponding author. Tel.: +1-859-257-1718; fax: +1-859-257- 7585; e-mail: pcrooks@uky.edu