Phenoxybenzamine Hydrochloride

Phenoxybenzamine hydrochloride binds irreversibly to α2-adrenergic receptors through covalent interaction with a cysteine residue in transmembrane domain 3. Irreversible binding of phenoxybenzamine to recombinant human α2A-, α2B-, and α2C-adrenergic receptors at 90 nM for 30 minutes reduced ligand binding capacity by 81, 96, and 77 percent respectively. When the TM3 cysteine Cys(117) of α2A-adrenergic receptor was mutated to valine, the receptor became resistant to phenoxybenzamine with only 10 percent inactivation. The beta2-adrenergic receptor contains a valine at this position and was not inactivated by phenoxybenzamine with 26 percent inactivation. Exchange of amino acids at positions 116 and 117 between α2A- and β2-adrenergic receptors confirmed that position 3.36 is exposed to receptor ligands while position 3.35 is not exposed in the binding pocket.

Fig. 1 Effect of preincubation with Phenoxybenzamine on ligand binding capacity. (Frang H.; et al. 2001)