Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists

The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure–activity relationship studies on the initial hit <b>1</b> have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor. Affinities and potencies of these compounds were confirmed in radioligand binding and functional cAMP assays. Two compounds, <b>16</b> and <b>33</b>, had good solubility and blood–brain barrier permeability that fall within the range of CNS permeant candidates without the liability of being a P-glycoprotein substrate. Finally, both compounds reversed fentanyl-induced hyperalgesia in rats when administered intraperitoneally. Together, these results point to the potential of these proline analogs as promising NPFF receptor antagonists

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

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 [³⁵S]­GTP-γ-S binding while enhancing [³H]­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

Selective blockade of the orexin-1 receptor (OX₁) 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 OX₁ selective antagonists. Aimed at elucidating structure–activity relationship requirements in other regions of the molecule and further enhancing OX₁ 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 OX₁ 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>_e) of 16.1 nM at the OX₁ receptor and >620-fold selectivity over the OX₂ receptor. In vivo, compound <b>73</b> was shown to block the development of locomotor sensitization to cocaine in rats