The preclinical pharmacologic activity of LY281067 shows it to be a potent and highly selective serotonergic (5-HT2) receptor antagonist. Based upon binding studies with 5-HT2 receptors in brain cortical membranes and block of 5-HT-induced contractions in the rat jugular vein, LY281067 showed high affinity at 5-HT2 receptors with a dissociation constant of approximately 1 nM. Furthermore, LY281067 was a highly selective 5-HT2 receptor antagonist without appreciably binding to 5-HT1, D1 or D2 receptors or interacting with histamine (H1), cholinergic, beta adrenergic or alpha-1 adrenergic receptors in smooth muscle. LY281067 had modest affinity at alpha-2 receptors with a dissociation constant of approximately 100 nM. Oral bioavailability of LY281067 in spontaneously hypertensive rats was excellent with an oral to i.v. dose ratio approximating 4, based upon blockade of pressor responses to 5-HT as an in vivo estimate of 5-HT2 receptor antagonist activity. Furthermore, LY281067 blocked quipazine-induced increase in serum corticosterone concentration, an increase thought to be mediated by activation of central 5-HT receptors. After oral administration to rats, LY281067 antagonized vascular 5-HT2 receptors with a relatively long duration of action (greater than 6 hr), an observation likely to be related to plasma concentrations of both the parent and an active metabolite. Lastly, LY281067 was relatively nontoxic, possessing a therapeutic index of approximately 1000 after oral administration to rats. In summary, LY281067 is a potent and highly selective, orally active 5-HT2 receptor antagonist with a relatively long duration and wide margin of therapeutic safety.