Bulk is a determinant of oxymetazoline affinity for the alpha1A-adrenergic receptor.
The alpha1A-adrenergic receptor (AR) has a higher affinity for several agonists and antagonists compared to alpha1B or alpha1D ARs. Mutagenesis studies were used to determine residues potentially responsible for this subtype selectivity. Oxymetazoline has a 50-fold lower affinity for alpha1D ARs compared to alpha1A ARs and also displayed a significant loss of affinity for an alpha1A Leu-290 to Phe mutant. It was concluded that steric interactions between the alpha1D ARs Phe-360 and the bulkytert-butyl group of oxymetazoline partially accounts for this lower affinity. Thus, the alpha1A AR binding pocket may more easily accommodate bulk at the paraposition of the phenyl ring than the alpha1D AR.
McCune
Dan
D
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Gaivin
Robert
R
Rorabaugh
Boyd
B
Perez
Dianne
D
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010109:Oxymetazoline / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D010109:Oxymetazoline