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: Helen A Kogan, Charles A Marsden, Kevin C F Fone
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 449 Issue 1-2 Pg. 105-11 (Aug 02 2002) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12163113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-Antagonists
• Blood Glucose
• DR-4004
• Dopamine Antagonists
• Indoles
• Phenols
• Pyridines
• Receptors, Biogenic Amine
• Receptors, Dopamine D2
• Receptors, Serotonin
• SB 269970
• Serotonin Antagonists
• Sulfonamides
• serotonin 7 receptor
• Raclopride
• Prazosin

Topics

• Adrenergic alpha-Antagonists (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Blood Glucose (metabolism)
• Body Temperature (drug effects)
• Dopamine Antagonists (pharmacology)
• Hypothalamus (drug effects, metabolism)
• In Vitro Techniques
• Indoles (pharmacology)
• Kinetics
• Male
• Phenols (pharmacology)
• Prazosin (pharmacology)
• Pyridines (pharmacology)
• Raclopride (pharmacology)
• Rats
• Receptors, Biogenic Amine (drug effects)
• Receptors, Dopamine D2 (drug effects)
• Receptors, Serotonin (drug effects)
• Serotonin Antagonists (pharmacology)
• Sulfonamides (pharmacology)