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Titolo:
Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity andselectivity in quinoline tachykinin receptor antagonists
Autore:
Blaney, FE; Raveglia, LF; Artico, M; Cavagnera, S; Dartois, C; Farina, C; Grugni, M; Gagliardi, S; Luttmann, MA; Martinelli, M; Nadler, GMMG; Parini, C; Petrillo, P; Sarau, HM; Scheideler, MA; Hay, DWP; Giardina, GAM;
Indirizzi:
SmithKline Beecham Pharmaceut, Dept Computat & Struct Sci, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AW ssex, England SmithKline Beecham SPA, Dept Med Chem, I-20021 Milan, Italy SmithKline Beecham SPA Milan Italy I-20021 ed Chem, I-20021 Milan, Italy SmithKline Beecham SPA, Dept Neurobiol Res, I-20021 Milan, Italy SmithKline Beecham SPA Milan Italy I-20021 iol Res, I-20021 Milan, Italy SmithKline Beecham Labs Pharmaceut, Unite Rech, F-35762 St Gregoire, France SmithKline Beecham Labs Pharmaceut St Gregoire France F-35762 re, France SmithKline Beecham Pharmaceut, Dept Pulm Biol, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 11, volume: 44, anno: 2001,
pagine: 1675 - 1689
SICI:
0022-2623(20010524)44:11<1675:SMONAN>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEMBRANE-SPANNING SEGMENT; BINDING-SITE CREVICE; PROTEIN-COUPLED RECEPTORS; DOPAMINE D2 RECEPTOR; BETA-ADRENERGIC-RECEPTOR; ALPHA-HELICES; NONPEPTIDE ANTAGONISTS; DIRECTED MUTAGENESIS; SUBSTANCE-P; RESIDUES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
63
Recensione:
Indirizzi per estratti:
Indirizzo: Giardina, GAM SmithKline Beecham Pharmaceut, Dept Computat & Struct Sci, New Frontiers Sci Pk,3rd Ave, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut New Frontiers Sci Pk,3rd Ave Harlow Essex England CM19 5AW
Citazione:
F.E. Blaney et al., "Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity andselectivity in quinoline tachykinin receptor antagonists", J MED CHEM, 44(11), 2001, pp. 1675-1689

Abstract

A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonistsusing the same 2-phenylquinoline template is described. Docking studies with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-( l-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin- l-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K-i = 0.8 nM; hNK-2R binding affinity, Ki = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N- 1,2,2-trimethylpropyl)-3- [(4-piperidin- l-yl)piperidin- l-yl] methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K-i = 193 nM; hNK-BR binding affinity, K-i = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 8-phenylquinoline chemical class. Since some members of this chemical series showed a significant binding affinity for the human mu -opioid receptor (hMOR), docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significant mu -opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 10:22:26