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

Mol Pharmacol. 2015 Dec;88(6):1024-34. doi: 10.1124/mol.115.101030. Epub 2015 Sep 18.


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 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 β1AR and β2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey β1AR and an inverse agonist of human β2AR. The structure of 7-methylcyanopindolol-bound β1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound β1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol-bound β1AR 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 β1AR. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / physiology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Pindolol / analogs & derivatives*
  • Pindolol / chemistry
  • Pindolol / metabolism
  • Pindolol / pharmacology
  • Protein Binding / physiology
  • Protein Structure, Secondary
  • Receptors, Adrenergic, beta-1 / chemistry*
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Structure-Activity Relationship
  • Turkey


  • Receptors, Adrenergic, beta-1
  • cyanopindolol
  • Pindolol