title: DR4004, a putative 5-HT(7) receptor antagonist, also has functional activity at the dopamine D2 receptor.
abstract: The tetrahydrobenzindole, 2a-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl)-2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one (DR4004) has been described as a highly selective antagonist for the 5-hydroxytryptamine(7) (5-HT(7)) receptor [J. Med. Chem. 42 (1999) 533]. Consistent with original data, DR4004 bound to rat hypothalamic membranes with an affinity of 7.3+/-0.2 (pK(i)+/-S.E.M.) for the 5-HT(7) receptor. However, competition binding studies showed that DR4004 had poor receptor selectivity with the following affinity profile; dopamine D2 receptor, alpha(1)-adrenoceptor > or =5-HT(7) receptor>histamine H(1) receptor, alpha(2)-adrenoceptor>dopamine D1 receptor>beta-adrenoceptor, muscarinic and 5-HT(2A/C) receptors. In conscious rats DR4004 (1, 5 or 10 mg/kg i.p.) produced a dose-dependent hyperglycaemia and hypothermia, but the former was reduced by the dopamine D2 receptor antagonist raclopride. Another 5-HT(7) receptor antagonist, (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) produced hypothermia but no hyperglycaemia. This study confirms that DR4004 has high affinity for the 5-HT(7) receptor but suggests that dopamine D2 receptor activity contributes to some of the in vivo effects.
authors.affiliation: School of Biomedical Sciences, Queen's Medical Centre, Nottingham University, Nottingham, NG7 2UH, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Kogan
authors.forename: Charles A
authors.initials: CA
authors.lastname: Marsden
authors.forename: Kevin C F
authors.initials: KC
authors.lastname: Fone
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D010636:Phenols / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017982:Receptors, Biogenic Amine / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; C472242:DR-4004; D018492:Dopamine Antagonists; D007211:Indoles; D010636:Phenols; D011725:Pyridines; D017982:Receptors, Biogenic Amine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D020891:Raclopride; D011224:Prazosin