Potent, semirigid nicotinic acetylcholine receptor agonists have been synthesized in order to better understand the acetylcholine receptor recognition sites. Numerous compounds, generally of the acetyl substituted piperidine and piperazine type, and bicyclic amines of the anatoxin-a type, have been prepared for structure- activity correlations. Computer assisted modeling studies have given minimum energy conformations, superimposability diagrams of the hydrogen bond acceptor and the cationic head onto the template, and electrostatic potentials at the van der Waals surfaces, providing additional information for a rational approach to the design of new, potent agonists. Isoarecolone (l-methyl-4-acetyl- 1,2,3,6-tetrahydropyridine) methiodide is the most potent of these synthetic nicotinic agonists as shown in various assays: (i) Torpedo electric tissue (high density of nicotnic receptors, (ii) frog rectus abdominus muscle (neuromuscular receptors), (iii) rat pheochromocytoma PC12 cells (ganglionic receptors), and (iv) rat brain membranes (central receptors). Also, isoarecolone hydrochloride produced nicotine-like discriminative effects in rats. Isoarecolone methiodide is only moderately potent at muscarinic M1 receptors (rat brain) in comparison to acetylcholine and exhibits weak activity at M2 receptors (heart). Nicotinic agonists and muscarinic agonists/antagonists may be useful in the treatment of cholinergic deficient diseases such as Alzheimer's disease, where reduced levels of acetylcholine, acetylcholine receptors and cholineacetyltransferase are found, and myasthenia gravis, where autoantibodies are directed to the main immunogenic region (MIR) of the alpha-subunit of the nicotinic receptor. A study of the effectiveness of isoarecolone salts in animal models of Alzheimer's disease (systemically and intracerebroventricularly) is in progress.
