DR4004, a putative 5-HT7 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-hydroxytryptamine7 (5-HT7) 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 (pKi±S.E.M.) for the 5-HT7 receptor. However, competition binding studies showed that DR4004 had poor receptor selectivity with the following affinity profile; dopamine D2 receptor, α1-adrenoceptor ≥5-HT7 receptor>histamine H1 receptor, α2-adrenoceptor>dopamine D1 receptor>β-adrenoceptor, muscarinic and 5-HT2A/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-HT7 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-HT7 receptor but suggests that dopamine D2 receptor activity contributes to some of the in vivo effects.