A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. In our SAR approach, the (4-chlorophenoxy)methyl group at C-2 was kept constant and a series of BIs substituted with various piperidinylalkyl groups at N-1 was synthesized to identify the optimal spacing and orientation of the piperidine ring nitrogen relative to the benzimidazole. The 3-(3-piperidinyl)propyl in 33 was found to maximize affinity for the Y1 receptor. Because of the critical importance of Arg33 and Arg35 of NPY binding to the Y1 receptor, the incorporation of an additional aminoalkyl functionality to the structure of 33 was explored. Methyl substitution was used to probe where substitution on the aromatic ring was best tolerated. In this fashion, the C-4 was chosen for the substitution of the second aminoalkyl functionality. Synthesis of such compounds with a phenoxy tether using the 4-hydroxybenzimidazole 11 was pursued because of their relative ease of synthesis. Functionalization of the hydroxy group of 45 with a series of piperidinylalkyl groups provided the dibasic benzimidazoles 55-62. Among them, BI 56 demonstrated a Ki of 0.0017 microM, which was 400-fold more potent than 33. To evaluate if there was a stereoselective effect on affinity for these BIs, the four constituent stereoisomers (69-72) of the BI 60 were prepared using the S- and R-isomers of bromide 17. Antagonist activity of these BIs was confirmed by measuring the ability of selected compounds to reverse NPY-induced forskolin-stimulated cyclic AMP. The high selectivity of several BI antagonists for the Y1 versus Y2, Y4, and Y5 receptors was also shown.
In this paper, we describe the synthesis of a series of alpha-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. We explored alkyl substitution, both normal and terminally branched; phenylalkyl and diphenylalkyl substitution; and a variety of aromatic and carbocyclic surrogates for phenyl. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin-stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. We found that while alkyl substitution provided no increase in affinity relative to 2, phenylethyl and diphenylethyl substitution, as in 105 and 109, respectively, were quite beneficial. The affinity of 109 was further enhanced when the two aromatic rings were joined by an oxygen or sulfur atom to form the tricyclic xanthylmethyl and thioxanthylmethyl amino acids 113 and 114, respectively. Amino acid 113, with an IC50 of 0.010 microM in the [3H]Glu binding assay, was 52-fold more potent than 2, whose IC50 was 0.47 microM.
We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.
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