Design, Synthesis, and Neurochemical Evaluation of 2-Amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines and 2-Amino-5-(alkoxycarbonyl)-1,4,5,6-tetrahydropyrimidines as M1 Muscarinic Receptor Agonists

• Published in: Journal of medicinal chemistry Vol. 37; no. 17; pp. 2774 - 2782
• Main Authors: Dunbar, Philip G, Durant, Graham J, Rho, Taikyun, Ojo, Babatunde, Huzl, James J. III, Smith, Douglas A, El-Assadi, Afif A, Sbeih, Sbeih, Ngur, Dan O
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1994
• Subjects: Alzheimer Disease - drug therapy; Animals; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Chemistry; Drug Design; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; In Vitro Techniques; Indicators and Reagents; Inositol - metabolism; Isomerism; Kinetics; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Conformation; Molecular Structure; Organic chemistry; Parasympathomimetics - chemical synthesis; Parasympathomimetics - chemistry; Parasympathomimetics - pharmacology; Phosphatidylinositols - metabolism; Preparations and properties; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - physiology; Spectrophotometry, Infrared; Structure-Activity Relationship; Agonist; Acetylenic compound; Alzheimer disease; Central nervous system; Modeling; M1 receptor; Biological activity; Pyridine derivatives; Amidine; Cholinergic receptor; Hydrochlorides; Least squares method; Racemate; Pyrimidine derivatives; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00043a016

Four regioisomers of 2-amino-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (2a-5a) were synthesized as the racemates to evaluate the utility of exocyclic amidines in the development of novel agonists for M1 muscarinic receptors. Of the four regioisomers, only racemic 2-amino-5-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (4a; CDD-0075-A) displayed high affinity (IC50 = 10 +/- 3.0 microM) and activity at muscarinic receptors coupled to PI metabolism in the rat cortex (260 +/- 4.5% stimulation above basal levels at 100 microM). A series of 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines then was synthesized for further evaluation as M1 agonists. Only the propargyl derivative (4d) retained substantial agonist activity (120 +/- 14% at 100 microM) in this series. On the basis of the activity of the 5-(alkoxycarbonyl)-1,4,5,6- tetrahydropyrimidines (1a and 1d) and the 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines, the corresponding cyclic guanidine derivatives were synthesized and tested. 2-Amino-5-(methoxycarbonyl)-1,4,5,6-tetrahydropyrimidine (7a) displayed a modest affinity for muscarinic receptors in the CNS (22 +/- 5.3 microM) and an ability to stimulate PI turnover in rat cerebral cortex (81 +/- 16% at 100 microM). The propargyl derivative (7d) also had modest binding affinity (31 +/- 15 microM) and high activity (150 +/- 8.5% at 100 microM), as expected based on the activity of propargyl esters of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine. Computational chemical studies revealed five distinct minimum-energy 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 five conformations for 1a could be superimposed upon a unique conformer of (R)-4a and 7a, suggesting that the compounds interact with muscarinic receptors in a similar fashion. Taken together, the data indicate the general utility of amidine systems as suitable replacements for the ammonium group of acetylcholine in developing ligands with activity at M1 muscarinic receptors in the central nervous system. Such compounds might be useful in the treatment of patients with Alzheimer's disease.