Affinity and intrinsic efficacy (IE) of 5'-carbamoyl adenosine analogues for the A1 adenosine receptor--efforts towards the discovery of a chronic ventricular rate control agent for the treatment of atrial fibrillation (AF) |
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Authors: | Palle Venkata P Varkhedkar Vaibhav Ibrahim Prabha Ahmed Hiba Li Zhihe Gao Zhenhai Ozeck Mark Wu Yuzhi Zeng Dewan Wu Lin Leung Kwan Chu Nancy Zablocki Jeff A |
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Institution: | Department of Bioorganic Chemistry, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304, USA. |
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Abstract: | The SAR for the affinity to the A(1) adenosine receptor and relative intrinsic efficacy (IE, (35)S]-GTPgammaS binding) of a series of 5'-carbamate and 5'-thionocarbamate derivatives of tecadenoson is described. Based on this SAR, selected compounds were evaluated in guinea pig isolated hearts to determine whether they were partial or full agonists with respect to their negative dromotropism, an A(1) AdoR mediated effect. Progress towards obtaining a partial A(1) AdoR agonist to potentially control ventricular rate during atrial fibrillation has been made with the discovery of several potent partial A(1) AdoR agonists (compounds 13, 14, and 17). |
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