Structure-Based SAR in the Design of Selective or Bifunctional Nociceptin (NOP) Receptor Agonists.

The nociceptin opioid receptor (NOP), the fourth member of the opioid receptor family, and its endogenous peptide ligand, nociceptin or orphanin FQ (N/OFQ), play a vital role in several central nervous system pathways regulating pain, reward, feeding, anxiety, motor control and learning/memory. Both selective NOP agonists as well as bifunctional agonists at the NOP and mu opioid receptor (MOP) have potential therapeutic applications in CNS disorders related to these processes. Using Surflex-Dock protocols, we conducted a computational structure-activity study of four scaffold classes of NOP ligands with varying NOP-MOP selectivity.

Discovery and Structure-Activity Relationships of Nociceptin Receptor Partial Agonists That Afford Symptom Ablation in Parkinson's Disease Models.

A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds , , and with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD.

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.

Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting.

The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats.

The strong reinforcing effects of nicotine and the negative symptoms such as anxiety experienced during a quit attempt often lead to relapse and low success rates for smoking cessation. Treatments that not only block the reinforcing effects of nicotine but also attenuate the motivation to relapse are needed to improve cessation rates. Recent genetic and preclinical studies have highlighted the involvement of the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits and the α3β4 nAChR subtype in nicotine dependence and withdrawal.

Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption.

Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate μ-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self-administer cocaine for 2 hours daily.

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations.

Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays. The action of the AT compounds were compared with standard NOP agonists (N/OFQ and Ro 65-6570) and the NOP selective antagonist SB-612111.

Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice.

Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice.

High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.

Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine.

AT-1001: a high-affinity α3β4 nAChR ligand with novel nicotine-suppressive pharmacology.

Background And Purpose: The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001.

Functional characterization of AT-1001, an α3β4 nicotinic acetylcholine receptor ligand, at human α3β4 and α4β2 nAChR.

Introduction: Genome-wide association studies linking the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits to nicotine dependence suggest that α3β4* nAChR may be targets for smoking cessation pharmacotherapies. We previously reported that AT-1001, a selective α3β4* nAChR ligand binds with high affinity to rat α3β4 and human α3β4α5 nAChR, antagonizes epibatidine-induced activation of rat α3β4 nAChR in HEK cells and potently inhibits nicotine self-administration in rats.

Methods: Two-electrode voltage clamp was used for functional characterization of AT-1001 at recombinant human α3β4 and α4β2 nAChR expressed in Xenopus oocytes.