Dunbar P G, Durant G J, Fang Z, Abuh Y F, el-Assadi A A, Ngur D O, Periyasamy S, Hoss W P, Messer W S
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606.
J Med Chem. 1993 Apr 2;36(7):842-7. doi: 10.1021/jm00059a008.
A series of 5-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines+ ++ (7a-h) was synthesized for biological evaluation as selective agonists for M1 receptors coupled to phosphoinositide (PI) metabolism in the central nervous system. Each ligand bound with high affinity to muscarinic receptors from rat brain as measured by inhibition of [3H]-(R)-quinuclidinyl benzilate ([3H]-(R)-QNB) binding. 5-(3-Methyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine+ ++ trifluoroacetate (CDD-0098-J;7a) displayed high affinity (IC50 = 2.7 +/- 0.69 microM) and efficacy at muscarinic receptors coupled to PI metabolism in the rat cortex and hippocampus. Increasing the length of the alkyl substituent increased affinity for muscarinic receptors yet decreased activity in PI turnover assays. The hippocampal PI response of 7a was blocked by lower concentrations of pirenzepine (8) or by higher concentrations of either AF-DX 116 (9) or p-fluorohexahydrosiladifenidol (10), suggesting that at low concentrations 7a selectively stimulates PI turnover through M1 receptors.
合成了一系列5-(3-烷基-1,2,4-恶二唑-5-基)-1,4,5,6-四氢嘧啶（7a - h），用于作为中枢神经系统中与磷酸肌醇（PI）代谢偶联的M1受体的选择性激动剂进行生物学评价。通过抑制[3H]-(R)-喹核醇苯甲酸酯（[3H]-(R)-QNB）结合测定，每个配体都与大鼠脑毒蕈碱受体具有高亲和力。5-(3-甲基-1,2,4-恶二唑-5-基)-1,4,5,6-四氢嘧啶三氟乙酸盐（CDD - 0098 - J；7a）在大鼠皮质和海马体中与PI代谢偶联的毒蕈碱受体上显示出高亲和力（IC50 = 2.7 +/- 0.69 microM）和效能。增加烷基取代基的长度增加了对毒蕈碱受体的亲和力，但降低了PI周转试验中的活性。7a的海马体PI反应被较低浓度的哌仑西平（8）或较高浓度的AF - DX 116（9）或对氟六氢硅二苯胺（10）阻断，表明在低浓度下7a通过M1受体选择性刺激PI周转。
