8 research outputs found

    Toward the Development of Bivalent Ligand Probes of Cannabinoid CB1 and Orexin OX1 Receptor Heterodimers

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    Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. Aimed at studying these complexes, a series of bivalent CB1 and OX1 ligands combining SR141716 and ACT-078573 pharmacophores were designed, synthesized, and tested for activity against CB1 and OX1 individually and in cell lines that coexpress both receptors. Compound <b>20</b> showed a robust enhancement in potency at both receptors when coexpressed as compared to individually expressed, suggesting possible interaction with CB1-OX1 dimers. Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo

    Truncated Orexin Peptides: Structure–Activity Relationship Studies

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    Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism, and reward. Development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. The goal of this study was to further investigate the structure–activity relationships of these peptides and to identify the truncated form of the orexin peptides active at OX<sub>1</sub>. Truncation studies have led to OXA (17–33) as the shortest active peptide known to date with a 23-fold selectivity for OX<sub>1</sub> over OX<sub>2</sub>. Alanine, d-amino acid, and proline scans have highlighted the particular importance of Tyr<sup>17</sup>, Leu<sup>20</sup>, Asn<sup>25</sup>, and His<sup>26</sup> for agonist properties of OXA(17–33). The conformation of the C-terminus might also be a defining factor in agonist activity and selectivity of the orexin peptides for the OX<sub>1</sub> receptor

    Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1‑(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1)

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    The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (<b>4</b>) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on <b>4</b>, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to <b>4</b>. These compounds increased the specific binding of [<sup>3</sup>H]­CP55,940, in agreement with previous reports. Importantly, <b>4</b> and two analogs dose-dependently reduced the <i>E</i><sub>max</sub> of the agonist curve in the CB1 calcium mobilization assays, confirming their negative allosteric modulator characteristics. Given the side effects associated with CB1 receptor orthosteric antagonists, negative allosteric modulators provide an alternative approach to modulate the pharmacologically important CB1 receptor

    Synthesis and Evaluation of Metabotropic Glutamate Receptor Subtype 5 Antagonists Based on Fenobam

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    In an effort to discover potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists, 15 tetrahydropyrimidinone analogues of 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-4,5-dihydro-1<i>H</i>-imidazol-2-yl)-urea (fenobam) were synthesized. These compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The IC<sub>50</sub> value for 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-1,4,5,6-tetrahydropyridine)­urea (<b>4g</b>) was essentially identical to that of fenobam

    Effect of 1‑Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin‑1 Receptor

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    Selective blockade of the orexin-1 receptor (OX<sub>1</sub>) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain’s reward system. We have recently reported a series of tetrahydroisoquinoline-based OX<sub>1</sub> selective antagonists. Aimed at elucidating structure–activity relationship requirements in other regions of the molecule and further enhancing OX<sub>1</sub> potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX<sub>1</sub> receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound <b>73</b> (RTIOX-251) with an apparent dissociation constant (<i>K</i><sub>e</sub>) of 16.1 nM at the OX<sub>1</sub> receptor and >620-fold selectivity over the OX<sub>2</sub> receptor. In vivo, compound <b>73</b> was shown to block the development of locomotor sensitization to cocaine in rats

    Identification of 1‑({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)‑1<i>H</i>‑pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound

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    Compounds active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects on different types of nociceptive modalities, including thermal, mechanical, and chemical stimuli. The NTS2 preferring peptide JMV-431 (<b>2</b>) and the NTS2 selective nonpeptide compound levocabastine (<b>6</b>) have been shown to be effective in relieving the pain associated with peripheral neuropathies. With the aim of identifying novel nonpeptide compounds selective for NTS2, we examined analogues of SR48692 (<b>5a</b>) using a FLIPR calcium assay in CHO cells stably expressing rat NTS2. This led to the discovery of the NTS2 selective nonpeptide compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1<i>H</i>-pyrazol-3-yl]­carbonyl}­amino)­cyclohexane carboxylic acid (NTRC-739, <b>7b</b>) starting from the nonselective compound <b>5a</b>

    Discovery of <i>N</i>‑{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

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    There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)­piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [<sup>35</sup>S]­GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold <b>21</b> was synthesized and tested for their ability to inhibit [<sup>35</sup>S]­GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to <i>N</i>-[(1<i>S</i>)-1-{[(3<i>S</i>)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]­methyl}-2-methylpropyl]-4-phenoxybenzamide (<b>11a</b>), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on <b>11a</b> provided 28 novel analogues. Evaluation of these 28 compounds in the [<sup>35</sup>S]­GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists

    Identification of 2‑({[1-(4-Fluorophenyl)-5-(2-meth­oxy­phen­yl)‑1<i>H</i>‑pyr­azol-3-yl]­carb­onyl}ami­no)tri­cyclo[3.3.1.13,7]­dec­ane-2-carb­oxy­lic Acid (NTRC-844) as a Selective Antagonist for the Rat Neurotensin Receptor Type 2

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    Neurotensin receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (<b>8</b>) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound <b>9</b> in the NTS2 binding assay
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