ASSOCIATION OF BETA-AGONISTS WITH CORRESPONDING BETA(2)-ADRENERGIC AND BETA(1)-ADRENERGIC PENTAPEPTIDE SEQUENCES

Synthesized beta1- and beta2-pentapeptide sequences corresponding to p ublished adrenoceptor transmembrane activation site subtypes were inve stigated in vitro for selectivity in association for drug ligands of k nown selectivity. Both nuclear magnetic resonance spectroscopy and mol ecular mechanics demonstrated that structural differences among the co rresponding pentapeptide activation-site sequences can explain agonist selectivity. Results suggest the agonists bind across the activation site loop on the second transmembrane alpha-helix by dipole/dipole int eractions between a ligand and the peptide. Since electrostatic intera ctions within the membrane may determine the rate of intercellular ion flux, agonist association across the activation site sequence. could thereby decrease electrostatic resistance to positive ion flux into th e cell. Interactions between the peptides and the ligands may provide insight into the structures and mechanisms involved in association of ligands for the identical sequences on the beta-adrenoreceptors.