PHOTOLABILE CAGED ADRENERGIC-RECEPTOR AGONISTS AND RELATED MODEL COMPOUNDS

The synthesis and photochemical characterization of caged derivatives of the adrenergic receptor agonists phenylephrine, epinephrine and iso proterenol are described. These compounds were prepared using 2-nitrob enzyl or substituted 2-nitrobenzyl photolabile protecting groups, and were designed to allow agonist concentration jumps to be made during p harmacological/physiological experiments. The advantage of this approa ch over conventional methods for changing the concentrations of agonis ts near receptors in mechanistic studies is the exquisite spatial and temporal resolution afforded by the use of light. Flash photolysis exp eriments revealed that photorelease is more than two orders of magnitu de faster when the 2-nitrobenzyl group is attached to the beta-amino g roup rather than one of the phenolic oxygens of the catecholamine. For the caged phenylephrine derivatives, for example, the rate constants of release from the N-linked and O-linked derivatives are 1.8 X 10(4) s(-1) and 1.1 x 10(2) s(-1) respectively. However, the quantum yields of photorelease from the N-linked and O-linked derivatives are similar . In addition, several model compounds were prepared to allow examinat ion of the effects of substituents on the aromatic ring and benzylic c arbon (of the 2-nitrobenzyl moiety) on the rates and efficiencies of p hotorelease. These studies revealed that, although substituents had li ttle effect on the rates of photorelease from the N-linked caged deriv atives, electron-donating groups on the 2-nitrobenzyl ring increased t he quantum yield of release by approximately fourfold, from 0.10 to 0. 40. A summary of the studies completed to evaluate the biological prop erties of the caged adrenergic receptor agonists is also presented.