Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Non-amines, drugs without an amine nitrogen, potently block serotonin transport: Novel antidepressant candidates?
Autore:
Goulet, M; Miller, GM; Bendor, J; Liu, SH; Meltzer, PC; Madras, BK;
Indirizzi:
Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Psychiat, Southborough, MA 01772 USA Harvard Univ Southborough MA USA 01772 ychiat, Southborough, MA 01772 USA Organix Inc, Woburn, MA 01801 USA Organix Inc Woburn MA USA 01801Organix Inc, Woburn, MA 01801 USA
Titolo Testata:
SYNAPSE
fascicolo: 3, volume: 42, anno: 2001,
pagine: 129 - 140
SICI:
0887-4476(200112)42:3<129:NDWAAN>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOPAMINE TRANSPORTER; MONOAMINE TRANSPORTERS; COCAINE ANALOG; HIGH-AFFINITY; 5-HYDROXYTRYPTAMINE TRANSPORTER; NEUROTRANSMITTER TRANSPORTERS; NONHUMAN-PRIMATES; MEMBRANE-VESICLES; BINDING-SITES; RECOGNITION;
Keywords:
antidepressants; serotonin reuptake; serotonin selective reuptake inhibitors; non-amines;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Madras, BK Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Psychiat, Southborough, MA 01772 USA Harvard Univ Southborough MA USA 01772 thborough, MA 01772 USA
Citazione:
M. Goulet et al., "Non-amines, drugs without an amine nitrogen, potently block serotonin transport: Novel antidepressant candidates?", SYNAPSE, 42(3), 2001, pp. 129-140

Abstract

The serotonin transporter (SERT) is a principal site of action of therapeutic antidepressants in the brain. Without exception, these inhibitors of serotonin transport contain an amine nitrogen in their structure. We previously demonstrated that novel compounds without an amine nitrogen in their structure (non-amines), blocked dopamine transport in cells transfected with the human dopamine transporter. The present study investigated whether, in the absence of an amine nitrogen, certain non-amines bind selectively to theSERT and block the transport of serotonin. At 10 muM concentration, selectnon-amines displayed no, or little, affinity for 9 serotonin, 5 dopamine, 7 adrenergic, 5 musearinic cholinergic, 3 opiate and histamine receptors. The affinities of non-amines for [H-3]citalopram binding sites on the SERT and their potencies for blocking [H-3]serotonin transport were measured in cloned human SERT stably or transiently expressed in HEK-293. Whether oxa- or carba-based, non-amines bound to [H-3]citalopram-labeled sites and blocked PHIserotonin transport in the low nanomolar range, at values equal to or higher than those of some conventional antidepressants. A non-amine, 0-1809, was 99-fold more selective for the serotonin over the dopamine transporter. As substituents on the aromatic ring of non-amines confer high affinity for the SERT, we investigated the hypothesis that aromatic-aromatic interactions may contribute significantly to non-amine/transporter association. A SERT mutant was produced in which a highly conserved aromatic amino acid, phenylalanine, 548, was replaced by an alanine (F548A). Although the affinities of several non-amines were unchanged in the mutant SERT, the affinity of imipramine was decreased, revealing possible differences in amine and non-amine binding domains on the SERT. The similar affinities of non-amines and conventional antidepressant drugs for the SERT support the view that an amine nitrogen is not essential for drugs to block serotonin transport with high affinity. Non-amines open avenues for developing a new generation of antidepressants. (C) 2001 Wiley-Liss, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 19:47:07