Design and Synthesis of Novel Derivatives of the Muscarinic Agonist Tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-Methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] Ether (CDD

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• 作者：Frederick R. Tejada ; Peter I. Nagy ; Min Xu ; Cindy Wu ; Tricia Katz ; Jason Dorsey ; Melissa Rieman ; Elizabeth Lawlor ; Manya Warrier ; William S. Messer ; Jr.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 14, 2006
• 年：2006
• 卷：49
• 期：25
• 页码：7518 - 7531
• 全文大小：513K
• 年卷期：v.49,no.25(December 14, 2006)
• ISSN：1520-4804

文摘

As part of a continuing effort to design and synthesize highly selective muscarinic agonists for differentmuscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized.Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol)and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, whichwas either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studiesalso were conducted to determine how the ligands interact with muscarinic receptors. The studies revealedthat varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increasebinding affinity for certain muscarinic receptor subtypes (at M₂ for 13d and M₄ for 1) and enhance functionalefficacy at M₄ receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessedby reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatmentof schizophrenia.