title: Remoxipride shows low propensity to block functional striatal dopamine D2 receptors in vitro.
abstract: The effect of remoxipride ((S)(-)3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzam ide) on dopamine D2 receptor-mediated inhibition of cAMP formation in rat striatal tissues pieces was established together with that of a number of other dopamine D2 receptor antagonists. The action of remoxipride, three other substituted benzamides, (-)-sulpiride, raclopride and NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylam ide mesylate) and haloperidol, a butyrophenone, was studied in the presence of (I) (+/-) SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (100 microM) plus pergolide (1 microM) or (II) forskolin (1 microM) plus dopamine (100 microM). In addition, four of the metabolites of remoxipride: FLA 797 ((S)-3-bromo-N[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6- methoxybenzamide), NCR 181 ((S)(-)-5-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6- methoxybenzamide tartrate), NCQ 436 ((S)(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dihydroxy-2- methoxybenzamide semioxalate) and NCQ 469 ((S)(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-hydroxy-2,6- dimethoxybenzamide hydrochloride), mainly found in rodents, were studied using test system I. The results demonstrate that remoxipride is significantly weaker in blocking functional striatal dopamine D2 receptors than either of the reference compounds studied and three of the four metabolites. The studies also demonstrate that dopamine D1 and D2 receptor interactions at the level of cAMP formation in the striatum are independent of action potentials or Ca2+.
authors.affiliation: Department of Neuropharmacology, CNS Preclinical R&D, Astra Arcus AB, Södertälje, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Westlind-Danielsson
authors.forename: K
authors.initials: K
authors.lastname: Gustafsson
authors.forename: I
authors.initials: I
authors.lastname: Andersson
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010479:Pergolide / Q000494:pharmacology; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D017330:Remoxipride / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D012457:Salicylamides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D017330:Remoxipride; C092943:NCQ 469; C084324:FLA 908; C084325:NCQ 436; D005576:Colforsin; D010479:Pergolide; D020891:Raclopride; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D013469:Sulpiride; C050313:FLA 797; D000242:Cyclic AMP; D006220:Haloperidol; D002118:Calcium; D004298:Dopamine; C064246:NCQ 298