TY - JOUR T1 - Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound β<sub>1</sub>-Adrenergic Receptor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.101030 SP - mol.115.101030 AU - Tomomi Sato AU - Jillian Baker AU - Tony Warne AU - Giles Brown AU - Andrew Leslie AU - Miles Congreve AU - Christopher Tate Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/09/21/mol.115.101030.abstract N2 - Comparisons between structures of the lower case β1-adrenergic receptor (β1AR) 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 β1AR 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 β1AR and β2AR. As predicted, the efficacy of 7-methylcyanopindolol was dramatically reduced compared to cyanopindolol, acting as a very weak partial 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-methylcyanopoindol-bound β1AR 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 cyanopindolol-bound β1AR. 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. ER -