RESUMEN
A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).
Asunto(s)
Iminas/síntesis química , Indoles/síntesis química , Receptor de Galanina Tipo 3/antagonistas & inhibidores , Animales , Unión Competitiva , Encéfalo/metabolismo , Células COS , Chlorocebus aethiops , AMP Cíclico/biosíntesis , Humanos , Iminas/farmacocinética , Iminas/farmacología , Indoles/farmacocinética , Indoles/farmacología , Ligandos , Ensayo de Unión Radioligante , Ratas , Receptor de Galanina Tipo 1/efectos de los fármacos , Receptor de Galanina Tipo 2/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have discovered high-affinity antagonists (exemplified by 11 and 12) that are the most selective for alpha(1d)-adrenergic receptors (alpha(1d)-AR) reported to date. In cloned receptor assay systems, 12 displays at least 95-fold selectivity for the alpha(1d)-AR over all other G-protein-coupled receptors tested, and the subtype selectivity of 11 was confirmed in pharmacologically defined isolated tissue preparations.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Piperazinas/síntesis química , Compuestos de Espiro/síntesis química , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Humanos , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Piperazinas/química , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Adrenérgicos alfa 1/fisiología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Bazo/efectos de los fármacos , Bazo/fisiología , Estereoisomerismo , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
The palladium-catalyzed coupling of the sodium salt of 7-amino-1,2,3-triazolo[4,5-d]pyrimidine (8-azaadenine, 1) with allylic phosphates or carbonates resulted in mixtures of 2- and 3-substituted 1,2,3-triazolopyrimidines, which were separated by chromatography. 1-Substituted triazolopyrimidines were not isolated from these reactions. Regioselectivity (and stereoselectivity) was also observed for substitution of the allylic moiety when more than one isomer is possible from the reaction. The use of 5-amino-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (8-azaguanine, 2), instead of 8-azaadenine, also resulted in mixtures. Alternate syntheses of the 3-allyl-1,2,3-triazolo[4,5-d]pyrimidines confirmed the structures of these compounds.
RESUMEN
Four of the previously reported compounds obtained from the acid-catalyzed condensation of indole with acetone are now assigned the following structures: cis-4,4a,9,9a-tetrahydro-2-(1H-indol-3-yl)-4,4-dimethyl-3H-carbazole (2a), 1,1',4,4'-tetrahydro-1,1,1',1'-tetramethyl-3,3'(2H,2'H)-spirobi[cyclopent[b]indole] (4), 4,4a-dihydro-2-(3-1H-indolyl)-4,4-dimethyl-3H-carbazol-4a-ol (7), and 5-(2-aminophenyl)-1,3,4,5-tetrahydro-1,1,4,4-tetramethylcyclopent[kl]acridine (8). The structure of the novel rearrangement product 8 was solved by an X-ray crystal structure determination. The two previously reported autoxidation products of 4 are now assigned the following structures: 1,3',4,4'-tetrahydro-1,1,4',4'-tetramethyl-cis-dispiro[cyclopent[b]indole-3(2H),2'(5'H)-furan-5',3"-[3H]-indol]-2"(1"H)-one (5) and 1,4-dihydro-1,1,5',5'-tetramethylspiro[cyclopent[b]indole-3(2H),3'(4'H)-1-benzazocine]-2'(1'H),6'(5'H)-dione (6).
RESUMEN
A series of amino analogs of 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (1) were synthesized to improve aqueous solubility, while retaining high affinity for the human galanin Gal3 receptor. A very potent analog (9e, 1,3-dihydro-1-[3-(2-pyrrolidinylethoxy)phenyl]-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one, Ki=5 nM) shows good selectivity and solubility of 48 microg/mL at pH 7.4.
Asunto(s)
Aminas/química , Indoles/química , Indoles/farmacología , Receptor de Galanina Tipo 3/efectos de los fármacos , Indoles/metabolismo , Receptor de Galanina Tipo 3/metabolismo , SolubilidadRESUMEN
The neuropeptide galanin mediates its effects through the receptor subtypes Gal(1), Gal(2), and Gal(3) and has been implicated in anxiety- and depression-related behaviors. Nevertheless, the receptor subtypes relevant to these behaviors are not known because of the lack of available galanin-selective ligands. In this article, we use behavioral, neurochemical, and electrophysiological approaches to investigate the anxiolytic- and antidepressant-like effects of two potent small-molecule, Gal(3)-selective antagonists, SNAP 37889 and the more soluble analog SNAP 398299. Acute administration of SNAP 37889 or SNAP 398299 enhanced rat social interaction. Furthermore, acute SNAP 37889 was also shown to reduce guinea pig vocalizations after maternal separation, to attenuate stress-induced hyperthermia in mice, to increase punished drinking in rats, and to decrease immobility and increase swimming time during forced swim tests with rats. Moreover, SNAP 37889 increased the social interaction time after 14 days of treatment and maintained its antidepressant effects during forced swim tests with rats after 21 days of treatment. In microdialysis studies, SNAP 37889 partially antagonized the galanin-evoked reduction in hippocampal serotonin (5-hydroxytryptamine, 5-HT), as did the 5-HT(1A) receptor antagonist WAY100635. Their combination produced a complete reversal of the effect of galanin. SNAP 398299 partially reversed the galanin-evoked inhibition of dorsal raphe cell firing and galanin-evoked hyperpolarizing currents. These results indicate that Gal(3)-selective antagonists produce anxiolytic- and antidepressant-like effects, possibly by attenuating the inhibitory influence of galanin on 5-HT transmission at the level of the dorsal raphe nucleus.