TY - JOUR T1 - Study of Interaction between Agonists and Asn293 in Helix VI of Human β<sub>2</sub>-Adrenergic Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 909 LP - 916 DO - 10.1124/mol.56.5.909 VL - 56 IS - 5 AU - Helene M. Zuurmond AU - Jutta Hessling AU - Klaus Blüml AU - Martin Lohse AU - Adriaan P. Ijzerman Y1 - 1999/11/01 UR - http://molpharm.aspetjournals.org/content/56/5/909.abstract N2 - Previously, we demonstrated the involvement of Asn293 in helix VI of the human β2-adrenergic receptor in stereoselective agonist recognition and activation. In the present study, we have further explored the role of this residue by synthesizing derivatives of isoproterenol and clenbuterol, two β-adrenergic receptor agonists. We analyzed their efficacy and affinity on the wild-type and a mutant receptor (Asn293Leu). Each compound had similar efficacy (τ values) on both the wild-type and mutant receptor, although τ values varied considerably among the eight compounds studied. It appeared that one derivative of isoproterenol, but not of clenbuterol, showed a gain in affinity from the wild type to the mutant receptor. This derivative had a methyl substituent instead of the usual β-OH group in the aliphatic side chain of isoproterenol, compatible with the more lipophilic nature of the leucine side chain. Such a “gain of function” approach through a combination of synthetic chemistry with molecular biology, may be useful to enhance our insight into the precise atomic events that govern ligand-receptor interactions. ER -