Preclinical studies on LY237733, a potent and selective serotonergic antagonist

8B-N-cyclohexyl-6-methyl-1(1-methylethyl)ergoline-8-carboxamide (LY237733) is an ergoline with potent and highly selective 5-hydroxytryptamine (5-HT) antagonist activity. The in vitro radioligand displacement studies showed that LY237733 has a preferential affinity for 5-HT1c and 5-HT2 receptors compared to other monoaminergic receptors. This characteristic is shared with other previously described ergoline 5-HT antagonists, such as LY53857 and sergolexole. In parallel ligand displacement assays, LY237733 had a similar potency to sergolexole. LY237733 was equipotent to sergolexole, but slightly less potent than LY53857 in the antagonism of 5-HT-induced elevation in blood pressure and quipazine-induced elevation in corticosterone levels, which are considered to be measures of 5-HT2 and possibly 5-HT1c antagonist activity. LY237733 failed to antagonize pergolide or 8-hydroxy-2-(di-n-propylamino)tetralin-induced elevations in serum corticosterone levels, indicating selectivity for the 5-HT1c/2 receptor, relative to 5-HT1a and D2 dopaminergic receptors. The only in vivo response that could be detected after administration of LY237733 alone in doses less than 1 mg/kg was the amplification of male rat sexual behavior. LY237733 was 10 to 100 times more potent than LY53857 or sergolexole in augmenting sexual responses of male rats with different levels of sexual response capacity. LY237733 has a much longer serum half-life than sergolexole. These studies have provided the pre-clinical rationale to evaluate the effects of this compound in the treatment of sexual disorders such as psychogenic erectile dysfunction, and other therapeutic indications for a 5-HT2 antagonist, including depression, anxiety, schizophrenia and migraine.