Discovery of a Novel Series of Orally Active Nociceptin/Orphanin FQ (NOP) Receptor Antagonists Based on a Dihydrospiro(piperidine-4,7′-thieno[2,3-<i>c</i>]pyran) Scaffold

Toledo, Miguel Ángel; Pedregal, Concepciòn; Lafuente, Celia; Dı́az, Nuria; Martinez-Grau, Marìa Ángeles; Jiménez, Alma; Benito, Ana; Torrado, Alicia; Mateos, Carlos; Joshi, Elizabeth; Kahl, Steven D.; Rash, Karen; Mudra, Daniel R.; Barth, Vanessa N.; Shaw, David B.; McKinzie, David L.; Witkin, Jeffrey M.; Statnick, Michael A.

doi:10.1021/jm500117r

Cited by 52 publications

(43 citation statements)

References 35 publications

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“…Self-administration of the natural reinforcer saccharin was also studied. Finally, using two chemically unrelated selective NOP antagonists, namely LY2817412 and SB-612111 (Rizzi et al, 2007;Toledo et al, 2014), we provided pharmacological confirmation of our findings in NOP receptor ( − / − ) rats.…”

Section: Introductionsupporting

confidence: 70%

“…, were synthesized at Lilly Research Laboratories according to previously published methods and dissolved in a formulation that consisted of a 1 : 1 mixture of distilled water and 1 M H 3 PO 4 Toledo et al, 2014). The compounds were first wet with 20% of water.…”

Section: Drugsmentioning

confidence: 99%

“…Drug doses were chosen based on our previous experience with this compound and published data (Rizzi et al, 2007;Toledo et al, 2014). Before the beginning of the treatment, rats were acclimated to gavage administration procedures for three consecutive days, during which they received distilled water to familiarize them with the injection procedure, after which the experiment began.…”

Section: Alcohol and Saccharin Self-administration Under Prmentioning

confidence: 99%

“…A 10 mg/kg dose of LY2817412 produced 55% receptor occupancy of NOP receptors in the brain 24 h after administration (Toledo et al, 2014).…”

Section: Alcohol and Saccharin Self-administration Under Prmentioning

confidence: 99%

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Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

Kallupi

Scuppa

Guglielmo

et al. 2016

Neuropsychopharmacol

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The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (− / − ) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP ( − / − ) rats selfadminister less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP ( − / − ). When NOP ( − / − ) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP ( − / − ) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol selfadministration in Wt rats but not in NOP ( − / − ) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.

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Section: Introductionsupporting

confidence: 70%

Section: Drugsmentioning

confidence: 99%

Section: Alcohol and Saccharin Self-administration Under Prmentioning

confidence: 99%

“…A 10 mg/kg dose of LY2817412 produced 55% receptor occupancy of NOP receptors in the brain 24 h after administration (Toledo et al, 2014).…”

Section: Alcohol and Saccharin Self-administration Under Prmentioning

confidence: 99%

See 2 more Smart Citations

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

Kallupi

Scuppa

Guglielmo

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…High receptor density has been identified throughout the rat CNS including the hypothalamus (Florin et al, 2000;Gehlert et al, 2006). Recently, we used a liquid chromatography-tandem mass spectrometry method (Pedregal et al, 2012;Toledo et al, 2014) to measure RO of novel NOP receptor antagonists in the hypothalamus of rats. After oral administration, LY2940094 potently occupied NOP receptors in the hypothalamus with an ED 80 of 3 mg/kg (E. Raddad et al, submitted manuscript).…”

Section: Discussionmentioning

confidence: 99%

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Statnick

Chen

Ansonoff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/nociceptin-opioid-peptide (NOP) receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioral models. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP receptor knockout mice. Moreover, NOP receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.

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Spiropiperidines

2018

Privileged Structures in Drug Discovery

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Discovery of a Novel Series of Orally Active Nociceptin/Orphanin FQ (NOP) Receptor Antagonists Based on a Dihydrospiro(piperidine-4,7′-thieno[2,3-c]pyran) Scaffold

Cited by 52 publications

References 35 publications

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Spiropiperidines

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