5 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

    Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6‑Pyrrolidinylpyridinyl Substitution

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    Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (<b>2</b>). Similar to <b>2</b>, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [<sup>35</sup>S]­GTP-γ-S binding while enhancing [<sup>3</sup>H]­CP55,940 binding to the CB1 receptor. Structure–activity relationship studies revealed that the pyridinyl ring of <b>2</b> could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. <b>34</b> (RTICBM-74) had similar potencies as <b>2</b> in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, <b>34</b> was more effective than <b>2</b> in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction

    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
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