The main objective has been to synthesize potent, semirigid nicotinic and muscarinic acetylcholine receptor agonists in order to further understand the receptor recognition sites. Numerous compounds, generally of the acetyl substituted piperidine, piperazine and bicyclic amine-type, have been prepared for structure-activity correlations. Computer assisted modeling studies have given minimum energy conformations, hydrogen bonding to cationic distances/ superpositions and electrostatic potentials, providing additional information for a rational approach to the design of new, potent agonists. Isoarecolone (1- methyl-4-acetyl-1,2,3,6-tetrahydropyridine) methiodide is a very potent nicotinic agonist as shown in various assays: (i) Torpedo electric tissue, (ii) TE671 human medulloblastoma cell line, frog rectus abdominus muscle and rat esophageal striated muscle (neuromuscular receptors), (iii) rat PC12 cells and guinea pig ileum (ganglionic receptors), (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 (brain) 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 ACh, AChR's and cholineacetyltransferase are found, and myasthenia gravis, where autoantibodies are directed to the main immunogenic region (MIR) of the alpha-subunit of the nicotinic AChR. We plan to study the effectiveness of the isoarecolone salts in animal models of Alzheimer's disease (systemically and intracerebroventricularly).
