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Publication Abstract from PubMed

Comparisons between structures of the lower case beta1-adrenergic receptor (beta1AR) 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. Cyanopindolol is a weak partial agonist of beta1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 7-methylcyanopindolol would reduce dramatically its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology analysed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both beta1AR and beta2AR. As predicted, the efficacy of 7-methylcyanopindolol was dramatically reduced compared to cyanopindolol, acting as a very weak partial of turkey beta1AR and an inverse agonist of human beta2AR. The structure of 7-methylcyanopindolol-bound beta1AR was determined to 2.4 A resolution and found to be virtually identical to the structure of cyanopindolol-bound beta1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 A in 7-methylcyanopoindol-bound beta1AR and the hydroxyl group of Ser5.46 is positioned 0.8 A further from the ligand with respect to the position of the Ser5.46 side chain in cyanopindolol-bound beta1AR. Thus the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared to cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared to antagonists.

Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound beta1-Adrenergic Receptor.,Sato T, Baker J, Warne T, Brown G, Leslie A, Congreve M, Tate C Mol Pharmacol. 2015 Sep 18. pii: mol.115.101030. PMID:26385885^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.