DR4004, a putative 5-HT₇ receptor antagonist, also has functional activity at the dopamine D2 receptor

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• 作者：Kogan ; Helen A. ; Marsden ; Charles A. ; Fone ; Kevin C.F.
• 关键词：5-HT₇ receptor ; 5-HT (5-hydroxytryptamine ; serotonin) ; Body temperature ; Plasma glucose ; Dopamine D2 receptor ; 5-HT₇ receptor antagonist
• 刊名：European Journal of Pharmacology
• 出版年：2002
• 出版时间：August 2, 2002
• 年：2002
• 卷：449
• 期：1-2
• 页码：105-111
• 全文大小：280 K

文摘

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 (pK_i±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>^6;-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-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.