Nicotine Analogs: Structure-Affinity Relationships For Central Nicotinic Acetylcholinergic Receptor Binding

Abstract

Cholinergic receptors are one of the oldest known populations of neurotransmitter receptors, and acetylcholine is their natural ligand. Shortly after the discovery of acetylcholinergic receptors it was realized that the actions of cholinergic agents could best be described by invoking two distinct populations of receptors: muscarinic acetylcholinergic receptors and nicotinic acetylcholinergic receptors (nAChRs). Investigations during the 1950s to the 1980s identified a number of interesting nAChR agonists and antagonists using, for the most part, isolated peripheral tissue or organ preparations. Indeed, nicotinic pharmacophores were identified and are still the subject of continuing investigations. Relatively less has been done with nAChRs at the level of the central nervous system. However, the last decade has witnessed a significant resurgence of interest in nAChRs, particularly in central nAChRs, for several reasons. Nicotinic receptors were identified in brain homogenates, and techniques and radioligands were developed for their investigation. Furthermore, there exists today a better understanding of the structure of nAChRs. These receptors are pentameric units that are directly associated with an ion channel. The receptors are composed of various a (α₂-α₉), β (β₁β₄), y, and δ subunit combinations (see Shacka and Robinson 1996; Holladay et al. 1997) and their exact composition likely dictates their pharmacology and binding characteristics. There is also a difference between peripheral and central nAChRs, and the major population of brain nAChRs appears to be of the α₄β₂ type. Further fueling the interest in central nAChRs is evidence that such receptors may be involved in appetite, memory, analgesia, and various other physiological processes as well as in anxiety, memory, and certain mental and neurological disorders (Arneric and Brioni 1998). Although nicotine (1a), a naturally occurring nAChR ligand, is associated with a variety of toxic side effects, there is no reason to believe that these side effects are inextricably linked to the beneficial effects of nicotinic ligands. Thus, we and others have begun investigations to identify the structureactivity relationships (SAR) for nicotinic agonist and antagonist activity, and structure-affinity relationships (SAFIR) for central nAChR binding, to ultimately develop novel nicotinic agents with greater selectivity and reduced toxicity that may be useful for disorders involving nAChRs.