Phenyliminoimidazolidines. Characterization of a class of potent agonists of octopamine-sensitive adenylate cyclase and their use in understanding the pharmacology of octopamine receptors.
Octopamine, a major aminergic neurotransmitter in invertebrates, exerts many of its actions through receptors which are associated with the activation of adenylate cyclase. The present study defines and characterizes a new class of potent octopamine agonists, the substituted phenyliminoimidazolidines (PIIs). Approximately 30 of these derivatives were examined for agonist and antagonist effects on the highly enriched and specific octopamine-sensitive adenylate cyclase present in the firefly light organ, as well as on adenylate cyclases present in other invertebrate and vertebrate tissues. Several derivatives were extremely active and some (e.g. 2,6-diethyl-PII) had potencies exceeding those of any previously described agonists of octopamine-sensitive adenylate cyclase. Stimulation by the potent PIIs was reversible, nonadditive to that caused by octopamine, and could be antagonized by antagonists such as cyproheptadine (Ki = 4 microM), phentolamine (Ki = 23 microM), and propranolol (Ki = 72 microM). These inhibitory constants agreed well with those for inhibiting octopamine stimulation. Certain PII derivatives acted as partial agonists and some as antagonists of octopamine stimulation. Structure-activity relationships revealed, among other things, that short-chain alkyl substitution in the 2- and 6-phenyl positions enhanced activity, as did further substitution of 4-halo, 4-methyl, or 4-hydroxy substituents. 4-Amino or N-alkyl substitution decreased activity. Structurally related benzylimidazoline derivatives such as tolazoline and naphazoline were partial octopamine agonists, generally less active than the PIIs. Comparison, in three invertebrate species, of the effects of the PIIs and two other chemical classes of octopamine agonists demonstrated clearcut differences in species responsiveness. Other comparative studies revealed that the agonist activity of the potent PIIs was specific for tissues containing an octopamine-sensitive adenylate cyclase; adenylate cyclases activated by dopamine or by beta 1- or beta 2-adrenergic agonists were unaffected by these compounds. Evaluation of the relative binding affinities of various PIIs for mammalian alpha-adrenergic receptors, as well as the ability of various antagonists to block PII binding, strongly suggested that the active PIIs are affecting a class of octopamine receptors distinct from mammalian alpha 1- or alpha 2-adrenergic receptors. These octopamine receptors also appeared distinct from mammalian 5-HT1 and 5-HT2 receptors. Correlative physiological studies in insects revealed that the active PIIs mimicked octopamine and were potent activators of light emission in the firefly light organ.(ABSTRACT TRUNCATED AT 400 WORDS)