DESIGN, SYNTHESIS, AND NEUROCHEMICAL EVALUATION OF INO-5-(ALKOXYCARBONYL)-3,4,5,6-TETRAHYDROPYRIDINES AND O-5-(ALKOXYCARBONYL)-1,4,5,6-TETRAHYDROPYRIMIDINES AS M(1) MUSCARINIC RECEPTOR AGONISTS

Four regioisomers of amino-(methoxycarbonyl)-3,4,5,6-tetrahydropyridin e (2a-5a) were synthesized as the racemates to evaluate the utility of exocyclic amidines in the development of novel agonists for M(1) musc arinic receptors. Of the four regioisomers, only racemic ino-5-(methox ycarbonyl)-3,4,5,6-tetrahydropyridine (4a; CDD-0075-A) displayed high affinity (IC50 = 10 +/- 3.0 mu M) and activity at muscarinic receptors coupled to PI metabolism in the rat cortex (260 +/- 4.5% stimulation above basal levels at 100 mu M). A series of ino-5-(alkoxycarbonyl)-3, 4,5,6-tetrahydropyridines then was synthesized for further evaluation as M(1) agonists. Only the propargyl derivative (4d) retained substant ial agonist activity (120 +/- 14% at 100 mu M) in this series. On the basis of the activity of the 5-(alkoxycarbonyl)-1,4,5,6-tetrahydropyri midines (1a and 1d) and the ino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydrop yridines the corresponding cyclic guanidine derivatives were synthesiz ed and tested. o-5-(methoxycarbonyl)-1,4,5,6-tetrahydropyrimidine (7a) displayed a modest affinity for muscarinic receptors in the CNS (22 /- 5.3 mu M) and an ability to stimulate PI turnover in rat cerebral c ortex (81 +/- 16% at 100 mu M). The propargyl derivative (7d) also had modest binding affinity (31 +/- 15 mu M) and high activity (150 +/- 8 .5% at 100 mu M), as expected based on the activity of propargyl ester s of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridi ne. Computational chemical studies revealed five distinct minimum-ener gy conformations for 1a, (R)-4a, and 7a, and three for 1d, (R)-4d, and 7d, each with a unique orientation of the ester moiety. Each of the f ive conformations for la could be superimposed upon a unique conformer of (R)-4a and 7a, suggesting that the compounds interact with muscari nic receptors in a similar fashion. Taken together, the data indicate the general utility of amidine systems as suitable replacements for th e ammonium group of acetylcholine in developing ligands with activity at M(1) muscarinic receptors in the central nervous system. Such compo unds might be useful in the treatment of patients with Alzheimer's dis ease.