Pharmacological analysis and structure determination of 7-methylcyanopindolol–bound b1-adrenergic receptor

Sato, Tomomi and Baker, Jillian G. and Warne, Tony and Brown, Giles A. and Leslie, Andrew and Congreve, Miles and Tate, Christopher G. (2015) Pharmacological analysis and structure determination of 7-methylcyanopindolol–bound b1-adrenergic receptor. Molecular Pharmacology, 88 (6). pp. 1024-1034. ISSN 1521-0111

Full text not available from this repository.


Comparisons between structures of the b1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser5.46, coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3 (tertbutylamino)-2-hydroxypropoxy]-1H-indole-2 carbonitrile (cyanopindolol) is a weak partial agonist of b1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3 (tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2 carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7- methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both b1AR and b2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey b1AR and an inverse agonist of human b2AR. The structure of 7-methylcyanopindolol–bound b1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound b1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol–bound b1AR and the hydroxyl group of Ser5.46 is positioned 0.8 Å further from the ligand, with respect to the position of the Ser5.46 side chain in cyanopindololbound b1AR. Thus, the molecular basis for the reduction in efficacy of 7 methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number:
Depositing User: Eprints, Support
Date Deposited: 22 Feb 2017 14:25
Last Modified: 04 May 2020 17:25

Actions (Archive Staff Only)

Edit View Edit View