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

Abstract

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.

The utility of muscarinic agonists in the treatment of alzheimer’s disease

“…Over the past decade, several selective muscarinic agonists were developed incorporating a 1,4,5, 6-tetrahydropyrimidine moiety (Dunbar et al, 1993;Dunbar et al, 1994;Ojo et al, 1996;. The novel amidine derivatives exhibit excellent agonist activity at M 1 receptors expressed in cell lines and in brain, and very low activity at M 3 receptors Messer et al, 2000).…”

A one-pot synthesis of highly substituted tetrahydropyridines from N-benzylidenemethanamines, dialkyl acetylenedicarboxylates and benzylidenemalononitriles

“…[1][2][3][4][5][6][7][8] Tetrahydropyridine derivatives are also useful against several metabolic disorders and human ailments. The prominent biological activities associated with this pharmacophore are antiparasitic, antimicrobial, anticancer and antiviral.…”

“…The prominent biological activities associated with this pharmacophore are antiparasitic, antimicrobial, anticancer and antiviral. Further, these are intricately involved in MAO based mechanism in Parkinson's disease, [2][3][4][5][6][7][8][9][10][11][12][13] as inhibitors of farnesyl transferase, 14 dihydroorate dehydrogenase 15,16 and also play key roles in many disease processes.…”

Aqueous phase synthesis of polysubstituted pyrimidines/pyrrolidines catalyzed by β-cyclodextrin

“…Pyrimidine derivatives are versatile building blocks in synthetic organic chemistry and many bioactive molecules [1][2][3][4] with pyrimidine skeleton served as M1 muscarinic receptor agonists for the treatment of Alzheimer's disease [5,6] and human immune deficiency virus (HIV) protease inhibitors [7]. Pyrimidine moiety is an important class of N-containing heterocyclic system [8,9], which exhibits wide spectrum of biological activities such as bactericidal [10], fungicidal [11], analgesic [12], anti-hypertensive [13], antimicrobial [14] and anti-infective properties [15].…”