L-646,462, a cyproheptadine-related antagonist of dopamine and serotonin with selectivity for peripheral systems.
The selectivity, peripheral vs. central actions, of the antidopaminergic agent L-646,462 was assessed in two ways. First, elevation of prolactin in serum (peripheral) and homovanillic acid in the striatum were measured in rats. L-646,462 was found to have a central/peripheral activity ratio of 143, whereas comparable values derived for haloperidol, metoclopramide and domperidone were 1.4, 9.4 and 1305, respectively. Second, the ID50 values required to block apomorphine-induced emesis in beagles (peripheral receptor-mediated response) were compared with those required to block apomorphine-induced stereotypy (central receptor-mediated response) in rats. Central/peripheral ID50 ratios of 234, 9.2, 129 and 7040 were obtained, respectively, for L-646,462, haloperidol, metoclopramide and domperidone. The selectivity of L-646,462 for peripheral serotonin (5-HT) receptors in rats was determined by measuring its effectiveness in blocking 5-HT-induced paw edema (peripheral response) and 5-hydroxytryptophan-induced head twitch (central response); a ratio of 114 was obtained. This value agrees nicely with the ratio of 143 derived in the rat ( vide supra) for peripheral selectivity for dopamine receptors. L-646,462 is, therefore, selective in vivo, preferentially blocking dopamine and 5-HT receptors located outside the blood-brain barrier. With regard to dopamine-receptors, L-646,462 was about equipotent and more selective than metoclopramide, while being less potent and less selective than domperidone. Unlike metoclopramide or domperidone, L-646,462 also possessed a reasonably potent 5-HT receptor antagonist effect in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors; D003533:Cyproheptadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists; D005769:Gastrointestinal Motility / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D011388:Prolactin / Q000097:blood; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D018492:Dopamine Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003533:Cyproheptadine; D004294:Domperidone; C041719:L 646462; D011388:Prolactin; D006220:Haloperidol; D008787:Metoclopramide; D001058:Apomorphine; D006719:Homovanillic Acid