3-arylimino-2-indolones are potent and selective galanin GAL3 receptor antagonists.

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).

Amino substituted analogs of 1-phenyl-3-phenylimino-2-indolones with potent galanin Gal3 receptor binding affinity and improved solubility.

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.

Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299.

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.

Synthesis and structure-activity relationship of fluoro analogues of 8-{2-[4-(4-methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as selective alpha(1d)-adrenergic receptor antagonists.

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.

Palladium-Catalyzed Allylic Coupling of 1,2,3-Triazolo[4,5-d]pyrimidines (8-Azapurines).

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.

Structure Determination of the Products from the Acid-Catalyzed Condensation of Indole with Acetone.

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).