AMESERGIDE AND STRUCTURALLY RELATED NOR-D-ERGOLINES - 5HT(2) RECEPTORINTERACTIONS IN THE RAT

A series of tricyclic (nor-D) partial ergolines were synthesized via a highly convergent enantiospecific strategy, ultimately arising from a racemic tricyclic ketone. Michael addition to an acrylamide, followed by reductive methylation, afforded the key intermediate. Selective de protection and oxidation provided the tricyclic ergoline. Vascular 5HT 2 receptor interactions for the partial ergolines were dramatically re duced compared to the parent ergoline, amesergide, as determined in vi vo by activation of a pressor response or blockade of 5HT-induced pres sor responses in pithed rats. The desisopropyl tricyclic ergolines pos sessed some modest pressor activity that was unlikely to be related to 5HT2 receptor activation since these compounds did not inhibit the pr essor response to serotonin. In contrast, the isopropyl tricyclic ergo lines exhibited no agonist activity, but inhibited the pressor respons e to serotonin at 1 mg/kg iv. The ergoline amesergide inhibited the pr essor response to serotonin in doses of 0.01-0.1 mg/kg iv. The homochi ral isopropyl tricyclic ergoline was more potent as a 5HT2 receptor an tagonist than the epimeric (unnatural stereochemistry) analogue. Thus, the isopropyl moiety on the indole nitrogen is important for vascular 5HT2 receptor affinity in the rat. Most importantly, these data sugge st that conformational rigidity of the ergoline D-ring is required for optimal 5HT2 receptor interactions in the rat.