Dunbar P G, Durant G J, Rho T, Ojo B, Huzl J J, Smith D A, el-Assadi A A, Sbeih S, Ngur D O, Periyasamy S
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606.
J Med Chem. 1994 Aug 19;37(17):2774-82. 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.
合成了2-氨基-（甲氧基羰基）-3,4,5,6-四氢吡啶（2a - 5a）的四种区域异构体的外消旋体，以评估环脒在开发新型M1毒蕈碱受体激动剂中的效用。在这四种区域异构体中，只有外消旋的2-氨基-5-（甲氧基羰基）-3,4,5,6-四氢吡啶（4a；CDD - 0075 - A）在大鼠皮层中对与磷脂酰肌醇（PI）代谢偶联的毒蕈碱受体表现出高亲和力（IC50 = 10±3.0微摩尔）和活性（在100微摩尔时比基础水平高260±4.5%的刺激）。然后合成了一系列2-氨基-5-（烷氧基羰基）-3,4,5,6-四氢吡啶，作为M1激动剂进行进一步评估。在该系列中，只有炔丙基衍生物（4d）保留了显著的激动剂活性（在100微摩尔时为120±14%）。基于5-（烷氧基羰基）-1,4,5,6-四氢嘧啶（1a和1d）以及2-氨基-5-（烷氧基羰基）-3,4,5,6-四氢吡啶的活性，合成并测试了相应的环胍衍生物。2-氨基-5-（甲氧基羰基）-1,4,5,6-四氢嘧啶（7a）对中枢神经系统中的毒蕈碱受体表现出适度的亲和力（22±5.3微摩尔），并且能够刺激大鼠大脑皮层中的PI周转（在100微摩尔时为81±16%）。如基于1,4,5,6-四氢嘧啶和2-氨基-3,4,5,6-四氢吡啶的炔丙基酯的活性所预期的那样，炔丙基衍生物（7d）也具有适度的结合亲和力（31±15微摩尔）和高活性（在100微摩尔时为150±8.5%）。计算化学研究揭示了1a、（R）-4a和7a有五种不同的最低能量构象，1d、（R）-4d和7d有三种，每种构象的酯部分都有独特的取向。1a的五种构象中的每一种都可以与（R）-4a和7a的一种独特构象叠加，这表明这些化合物以相似的方式与毒蕈碱受体相互作用。综上所述，数据表明脒系统作为乙酰胆碱铵基团的合适替代物在开发对中枢神经系统中M1毒蕈碱受体有活性的配体方面具有普遍效用。这类化合物可能对治疗阿尔茨海默病患者有用。
