Novel bivalent ligands carrying potential antinociceptive effects by targeting putative mu opioid receptor and chemokine receptor CXCR4 heterodimers.

The functional interactions between opioid and chemokine receptors have been implicated in the pathological process of chronic pain. Mounting studies have indicated the possibility that a MOR-CXCR4 heterodimer may be involved in nociception and related pharmacologic effects. Herein we have synthesized a series of bivalent ligands containing both MOR agonist and CXCR4 antagonist pharmacophores with an aim to investigate the functional interactions between these two receptors. In vitro studies demonstrated reasonable recognition of designed ligands at both respective receptors. Further antinociceptive testing in mice revealed compound 1a to be the most promising member of this series. Additional molecular modeling studies corroborated the findings observed. Taken together, we identified the first bivalent ligand 1a showing promising antinociceptive effect by targeting putative MOR-CXCR4 heterodimers, which may serve as a novel chemical probe to further develop more potent bivalent ligands with potential application in analgesic therapies for chronic pain management.

Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats.

RATIONALE: GABAA positive allosteric modulators (GABAA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABAA PAMS may have lower abuse liability while retaining clinical utility. OBJECTIVE: The present study compared abuse-related effects of the non-selective GABAA PAM diazepam, the α1-selective GABAA PAM zolpidem, and three novel GABAA PAMs (JY-XHe-053, XHe-II-053, and HZ-166) using intracranial self-stimulation (ICSS) in rats. These novel compounds have relatively low efficacy at α1-, α2-, and α3-containing GABAA receptors, putative in vivo selectivity at α2/α3-containing GABAA receptors, and produce anxiolytic-like effects with limited sedation in non-human primates. METHODS: Adult, male Sprague-Dawley rats (n = 17) were each implanted with a bipolar electrode in the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule of reinforcement for electrical brain stimulation. The potency and time course of effects were compared for diazepam (0.1-10 mg/kg), zolpidem (0.032-3.2 mg/kg), and the three novel compounds (JY-XHe-053, XHe-II-053, and HZ-166; all 3.2-32 mg/kg). RESULTS: Zolpidem and diazepam produced transient facilitation of ICSS at small doses and more sustained rate-decreasing effects at larger doses. JY-XHe-053 and HZ-166 produced weak and inconsistent ICSS facilitation, whereas XHe-II-053 had no effect on ICSS. CONCLUSIONS: These results support a key role for α1-containing GABAA receptors in mediating GABAA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABAA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABAA PAMs.

Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats.

Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague-Dawley rats (n=12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0-10mg/kg) and MDPV (3.2mg/kg) facilitated ICSS. RTI-118 (3.2-32mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25-0.5mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV.