Alpha‐2 Adrenergic Receptor Homology Models Using Rhodopsin or Beta‐2 Adrenergic Receptor Templates

Alpha‐2 adrenergic receptor agonists are used as adjuncts to general anesthetics and in the pharmacological treatment of many disorders, including hypertension and attention‐deficit hyperactivity disorder. Clinically available alpha‐2 agonists are not subtype‐selective and their use is limited by adverse effects resulting from actions at non‐targeted subtypes. To develop subtype‐selective ligands for alpha‐2A, ‐2B, or ‐2C receptors, more binding site structural information is needed; however, the only high‐resolution crystal structures of GPCRs are of bovine rhodopsin and modified human beta‐2 and turkey beta‐1 adrenergic receptors. Our goal was to develop homology models of the alpha‐2 receptor subtypes, using either the rhodopsin or beta‐2 receptor crystal structure as a template, that are capable of identifying characteristics important in ligand binding. Alpha‐2A and ‐2C amino acid sequences were each aligned with each template sequence and homology models were created using Sybyl7.1. Fifteen alpha‐2 agonists, including catecholamines and imidazoline derivatives, were docked into the models using FlexiDock. A comparison of calculated binding energies with experimental binding affinities resulted in poor correlations in models of alpha‐2A (r2 = 0.396 and 0.606 for rhodopsin‐ and beta‐2‐based, respectively) and alpha‐2C (r2 = 0.349 and 0.338).Supported by a gift from Procter and Gamble.