Structural and steric requirements for beta-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in the rat limbic forebrain.

The present studies were undertaken to assess the structural and steric requirements for beta-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in slices of the rat limbic forebrain. Significant agonist activity of beta-phenethylamines requires a beta-3,4-dihydroxyphenethylamine with a beta-hydroxyl group in the R configuration. Thus, dopamine did not stimulate the system at concentrations up to 10(-3) M. Moreover, beta-hydroxyphenethylamines without a 3,4-catechol group (octopamine, phenylephrine, p-hydroxynorephedrine, metaraminol and methoxamine) - though exerting alpha-agonist activity in peripheral tissues - lack agonist activity in this particular cyclic AMP generating system. The effects of (R)-norepinephrine and (R)-isoproterenol at maximal concentrations were not additive. The results lend further support to the view that the cyclic AMP generating system in slices of the limbic forebrain is part of a norepinephrine receptor coupled adenylate cyclase system with a subpopulation of receptors that are beta in nature.