Effects of iminodibenzyl antipsychotic drugs on cerebral dopamine and alpha-adrenergic receptors.
The iminodibenzyl antipsychotic drugs, clocapramine, carpipramine and Y-516 were studied in order to elucidate their mechanisms of action. They all accelerated the accumulation of the dopamine (DA) metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatum and nucleus accumbens of the rat brain. Only Y-516 antagonized in vivo the apomorphine-induced inhibition of DA synthesis as estimated from the accumulation of 3,4-dihydroxyphenylalanine (DOPA) in the decarboxylase-inhibited rat striatum after cessation of nerve impulse flow. All three drugs showed high affinity for DA receptors labelled by [3H]haloperidol and [3H]ADTN in the rat striatum in vitro, with the order of potency Y-516 greater than clocapramine greater than carpipramine. All accelerated the accumulation of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in mouse brain. They showed high affinity for alpha 1-adrenoceptors labelled by [3H]WB 4101 and for alpha 2-adrenoceptors labelled by [3H]clonidine in the rat cerebral cortex in vitro. Although they all had the same level of affinity for the alpha 1-adrenoceptors, Y-516 had less affinity for the alpha 2-adrenoceptors than did clocapramine and carpipramine. The above results indicate that these drugs are potent DA antagonists which block alpha 1- and alpha 2-adrenoceptors in the brain.
Setoguchi
M
M
Sakamori
M
M
Takehara
S
S
Fukuda
T
T
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D001569:Benzodiazepines; D003342:Corpus Striatum / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D001552:Benzazepines; D003984:Dibenzazepines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C046384:mosapramine; D001569:Benzodiazepines; D012701:Serotonin; D008734:Methoxyhydroxyphenylglycol; C011639:ADTN; D004295:Dihydroxyphenylalanine; C000449:3-chlorocarpipramine; C006922:carpipramine; D004298:Dopamine; D009638:Norepinephrine