RECEPTOR INTERACTIONS OF IMIDAZOLINES .9. CIRAZOLINE IS AN ALPHA-1 ADRENERGIC AGONIST AND AN ALPHA-2 ADRENERGIC ANTAGONIST

Abstract

The .alpha.-1 and .alpha.-2 adrenergic effects of cirazoline were evaluated in guinea pig aorta and field stimulated guinea pig ileum, respectively. Cirazoline was a full agonist at .alpha.-1 receptors having an ED50, Ka and relative efficacy similar to that of (-)-norepinephrine [NE]. Cirazoline does not possess agonist activity at pre-synaptic .alpha.-2 receptors in the guinea pig ileum. While NE and cirazoline both inhibited the twitch response of the field-stimulated ileum, only the response to NE was blocked by the selective .alpha.-2 antagonist, yohimbine. The noradrenergic inhibition of the twitch response observed in the ileum with cirazoline resulted from weak anticholinergic activity (antimuscarinic) at the level of the postsynaptic effector organ and was observed only at high concentrations. At concentrations far below the level required to inhibit the twitch response, cirazoline competitively antagonized the .alpha.-2-mediated inhibition of the twitch response elicited by NE. A Schild plot analysis indicated that cirazoline is a potent competitive .alpha.-2 receptor antagonist characterized by a pA2 [competitive antagonistic activity] value (i.e., -log KB) of 7.56. Cirazoline is unique among imidazolines in that it is a potent .alpha.-1 adrenergic receptor agonist and an even more potent .alpha.-2 receptor antagonist. This unusual combination of activities could make cirazoline a particularly effective vasoconstricting agent.