Recent advances have been made in the understanding of the cholinergic nervous system and the receptors therein. These cholinergic receptors are proteins that are embedded in the cell membrane and respond to the chemical acetylcholine. In general there are two types of cholinergic receptors, nicotinic and muscarinic. Each receptor responds to acetylcholine, but they may respond to a different set of agonists and antagonists. Furthermore, cholinoceptive cells with nicotinic and muscarinic receptors may be located in different regions of the nervous system.
Muscarinic and nicotinic receptors mediate a wide variety of physiological responses to the neurotransmitter acetylcholine in the central and peripheral nervous systems. For example, M1 muscarinic receptors play a role in learning and memory function in the brain and regulate gastric acid secretion in the stomach. M2 receptors regulate acetylcholine release in the central nervous system and control cardiac muscle contraction in the heart. M3 receptors help regulate smooth muscle contraction in a variety of tissues and promote secretion from exocrine glands. M4 receptors are thought to play a role in the perception of pain, while M5 receptors are believed to regulate dopaminergic activity in the brain.
Several compounds have been developed synthetically or derived from natural products that bind to muscarinic receptor subtypes. Representative examples from natural products include atropine and scopolamine. As it was found that atropine and scopolamine are both bicyclic amines, several research groups have evaluated other bicyclic amines and their biological activities on cholinergic receptors. Several research groups have also studied and synthesized azabicyclic compounds. See, e.g., Sternbach et al., J. Am. Chem. Soc., “Antispadmodics. Bicyclic Basic Alcohols”, 74: 2215-2218 (1952); Sternbach et al., J. Am. Chem. Soc., “Antispadmodics. Esters of Basic Bicyclic Alcohols”, 74: 2219-2221 (1952); Martel et al., “Esters of Bicyclic Aminoalcohols as Potential Anticholinergics III”, Journal of Pharmaceutical Sciences, 52: 331-336 (1963); U.S. Pat. No. 4,870,081, issued to Orlek et al; and U.S. Pat. No. 5,468,875, issued to Sabb et al. Yet, despite the synthesis of these compounds, there still remains a need to find compounds that better regulate the cholinergic receptor.
In addition to the study of bicyclic amines, other references have noted the presence of two pharmacophores within a single muscarinic ligand. A bivalent muscarinic agonist was reported wherein two identical 1,2,5-thiadiazole derivatives were linked to provide a novel series of potent agents. See, e.g., Rajeswaran et al., “Design, Synthesis, and Biological Characterization of Bivalent 1-Methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole Derivatives as Selective Muscarinic Agonists”, J. Med. Chem., 44, 4563-4576 (2001); Christopoulos et al., “Synthesis and Pharmacological Evaluation of Dimeric Muscarinic Acetylcholine Receptor Agonists”, J. Pharmac. Exp. Therap., 298, 1260-1268 (2001). Further research into compounds that may include a dual pharmacophore presence may result in compounds that better regulate cholinergic receptors.
Despite the general knowledge regarding the use of cholinergic receptor subtypes, there are relatively few ligands that selectively or specifically interact with individual muscarinic receptor subtypes. Therefore, it may be advantageous to create new cholinergic receptor ligands that may be able to function as muscarinic or nicotinic receptor ligands.
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