Dataset Information

Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound ?1-Adrenergic Receptor.

ABSTRACT: Comparisons between structures of the ?1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser(5.46), coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of ?1AR 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 ?1AR and ?2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey ?1AR and an inverse agonist of human ?2AR. The structure of 7-methylcyanopindolol-bound ?1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound ?1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol-bound ?1AR and the hydroxyl group of Ser(5.46) is positioned 0.8 Å further from the ligand, with respect to the position of the Ser(5.46) side chain in cyanopindolol-bound ?1AR. 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.

SUBMITTER: Sato T

PROVIDER: S-EPMC4658595 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound β1-Adrenergic Receptor.

Sato Tomomi T Baker Jillian J Warne Tony T Brown Giles A GA Leslie Andrew G W AG Congreve Miles M Tate Christopher G CG

Molecular pharmacology 20150918 6

Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser(5.46), coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of β1AR and, based on the hypothesis above, we predicted that the addition of a me ...[more]

PMID: 26385885

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Dataset Information

Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound ?1-Adrenergic Receptor.

Publications

Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound β1-Adrenergic Receptor.

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