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Titolo:
5-HT1B D RECEPTOR ANTAGONISTS
Autore:
PAUWELS PJ;
Indirizzi:
CTR RECH PIERRE FABRE,MOL & CELLULAR NEUROBIOL LAB,17 AVE JEAN MOULINF-81106 CASTRES FRANCE
Titolo Testata:
General pharmacology
fascicolo: 3, volume: 29, anno: 1997,
pagine: 293 - 303
SICI:
0306-3623(1997)29:3<293:5DRA>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
DORSAL RAPHE NUCLEUS; TERMINAL SEROTONIN AUTORECEPTOR; NEUROGENIC PLASMA EXTRAVASATION; RECOMBINANT HUMAN 5-HT1D-ALPHA; CLONED HUMAN 5-HT1D-ALPHA; 5-HT(1B) BINDING-SITES; CALF SUBSTANTIA NIGRA; PIG FRONTAL-CORTEX; GUINEA-PIG; ADENYLATE-CYCLASE;
Keywords:
5-HT1B/D; RECEPTOR ANTAGONIST; 5-HT NEUROTRANSMISSION;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
135
Recensione:
Indirizzi per estratti:
Citazione:
P.J. Pauwels, "5-HT1B D RECEPTOR ANTAGONISTS", General pharmacology, 29(3), 1997, pp. 293-303

Abstract

1. 5-Hydroxytryptamine 1B (5-HT1B, formerly designated 5-HT1D beta) and 5-hydroxytryptamine-1D (5-HT1D, formerly designated 5-HT1D alpha) receptors are distinct molecular entities that mediate serotonergic neurotransmission. Both are G-protein-coupled receptors without introns in their coding region, negatively coupled to adenylate cyclase; their precise function in human beings remains to be defined, In brain, theyare highly enriched in the globus pallidus and the substantia nigra. 2. Presynaptic 5-HT1B/D receptors take part in the control of the release not only of 5-HT itself, but also of other neurotransmitters-for example, acetylcholine, glutamate, dopamine, noradrenaline and gamma-aminobutyric acid. Selective blockade of central 5-HT1B/D autoreceptors should facilitate 5-HT neurotransmission and may offer a novel approach to antidepressant therapy. Other 5-HT1B/D receptors are located postsynaptically; those receptors may be supersensitive in the pathophysiology of obsessive-compulsive disorder and may be a potential target for its treatment. 3. Few if any ligands show selectivity for 5 HT1B or 5-HT1D receptors or both. Most pharmacological studies have been performed with nonselective antagonists-for example, metergoline, 1-naphthylpiperazine, methiothepin, ketanserin and ritanserin. Recently, a never series of benzanilides have been reported as the first examples of selective 5-HT1B/D receptor antagonists. GR 127935, a representative compound of this series, displays mixed agonist antagonist properties both in vitro and in vivo. It induces upon systemic administration in the guinea pig either an opposite (decrease) effect or a small increase (65%, 5 mg/kg) in the concentration of cortical extracellular 5-HT compared with fiuoxetine (218%, 10 mg/kg). The importance of blockade of 5-HT1B/D receptors in the raphe region, their possible interaction with 5-HT1A receptors, and consequent inhibition of 5-HT release in terminal 5-HT1B/D receptor containing regions are discussed. 4. To find outwhether the available so-called 5-HT1B/D receptor antagonists are indeed antagonists and not partial agonists, efficacy was measured at recombinant human 5-HT1B and 5-HT1D receptor sites by using a [S-35]-GTP gamma S binding assay to membrane preparations of stably transfected rat C6-glial cell lines. Metergoline and the selective 5-HT1B/D receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic activity (43% to 69%) at the 5-HT1D receptor subtype, whereas the nonselective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsic activity at both receptor subtypes. In contrast, the nonserective ligands methiothepin, ketanserin and ritanserin are inverse agonists because they displayed negative efficacy (-14% to -28%). Differential blockade of 5-HT1B/D receptors by neutral antagonists and inverse agonists is discussed in relation to the 5-HT tone on 5-HT1B/D receptors. 5. It can be concluded that 5-HT1B/D receptor ligands modulate 5-HT neurotransmission through a terminal 5-HT1B/D receptor. Future work shouldbe directed toward the identification of selective 5-HT1B and 5-HT1D receptor ligands that display either neutral antagonist or inverse agonist properties to evaluate the therapeutic potential of 5-HT1B/D receptor blockade. (C) 1991 Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 08:37:46