Rapid release of an alpha-adrenergic receptor ligand from photolabile analogues.

A series of 2-nitrobenzyl derivatives of the alpha 1-selective adrenergic agonist, L-phenylephrine [(R)-N-[2-(3-hydroxyphenyl)-2-hydroxyethyl]-N-methylammonium chloride], have been synthesized and characterized for the purpose of developing biologically inert compounds that can be rapidly converted to L-phenylephrine by near-UV irradiation. The compounds, derivatized on the phenolic oxygen, were O-(1-(2-nitrophenyl)ethyl)phenylephrine (I), O-(2-nitrobenzyl)phenylephrine (II), O-(4,5-dimethoxy-2-nitrobenzyl)phenylephrine (III), and O-(alpha-carboxyl-2-nitrobenzyl)phenylephrine (IV). All four compounds photolyzed to free phenylephrine following a brief exposure to 300-350-nm light or 347-nm laser light with steady-state quantum yields ranging from 0.05 to 0.28. The rates of phenylephrine formation on photolysis were estimated from the decay rates of aci-nitro intermediates detected by absorbance between 380 and 500 nm. Compound IV displayed the highest quantum yield (0.28) and most rapid photolysis rate (1980 s-1) measured under near physiological conditions, pH 7.0, 22 degrees C. Biological properties of the compounds were examined in smooth muscle from rat caudal artery. Laser pulse photolysis of IV at 347 nm initiated a maximal contraction in Krebs buffer, pH 7.1, 25 degrees C, that mimicked the response to 50 microM phenylephrine but was faster in onset. Photoinitiated contractions were characterized by a delay of 0.93 +/- 0.09 s followed by a rising phase with a 10-90% rise time of 3.56 +/- 0.17 s (n = 7). Responses were fully blocked by the alpha 1-selective antagonist prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)