8-Acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists

Wichmann, Jürgen; Adam, Geo; Röver, Stephan; Cesura, Andrea M.; Dautzenberg, Frank M.; Jenck, F.

doi:10.1016/s0960-894x(99)00385-6

Cited by 57 publications

(56 citation statements)

References 12 publications

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“…In recent years, the techniques of combinatorial chemistry and high-throughput screening have been combined to identify compounds that act as potent agonists and antagonists of the ORL 1 receptor. Several small molecule agonists have been described for ORL 1 receptors that mimic the in vivo effects of nociceptin and are able to penetrate the blood-brain barrier [60][61][62]. The most selective of these appears to be compound Ro 64-6198.…”

Section: Orl 1 Receptor Ligandsmentioning

confidence: 99%

The ORL<sub>1</sub> Receptor: Molecular Pharmacology and Signalling Mechanisms

New

Wong²

2002

Neurosignals

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The cloning of the opioid-receptor-like 1 (ORL₁) receptor and the identification of nociceptin as its endogenous agonist have revealed a new G-protein-coupled receptor signalling system. The structural and functional homology of ORL₁ to the opioid receptor systems has posed a number of challenges in understanding the often competing physiological responses elicited by these G-protein-coupled receptors. Thus, this review will attempt to summarize recent research by many groups that has revealed numerous subtleties of the ORL₁ receptor and its signalling pathways, as well as document the efforts to produce high-affinity selective ligands for the ORL₁ receptor that may be of value as research and therapeutic tools.

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Section: Orl 1 Receptor Ligandsmentioning

confidence: 99%

The ORL<sub>1</sub> Receptor: Molecular Pharmacology and Signalling Mechanisms

New

Wong²

2002

Neurosignals

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“…Although Ro 65-6570 was found to show anxiolytic effects in an elevated plus-maze test (Wichmann et al, 1999), it was only 5 to 10-fold selective over μ receptors . Ro 64-6198, on the other hand, is far more selective and has shown an impressive anxiolytic profile comparable to benzodiazepines, in several in vivo anxiety paradigms .…”

Section: Spiropiperidinesmentioning

confidence: 93%

“…The lead compound 11 (Fig. 5) was a potent but nonselective ligand at hORL1 and also a full agonist in functional assays (Adam et al, 1998;Rover et al, 2000a;Wichmann et al, 1999). Replacement of the 2-tetralinyl piperidine nitrogen susbtituent with the larger acenaphthyl group (to give Ro 65-6570) and the even bulkier hexahydrophenalenyl group (to give Ro 64-6198) resulted in subnanomolar affinity ORL1 ligands, with >100-fold selectivity over the opioid receptors.…”

Section: Spiropiperidinesmentioning

confidence: 99%

Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: Research tools and potential therapeutic agents

Zaveri

2003

Life Sciences

109

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The 17-amino acid neuropeptide nociceptin/Orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioid receptor-like (ORL1) receptor, a fourth member of the classical μ, δ, and κ opioid receptor family. Although ORL1 clearly belongs to the opioid receptor family, it does not bind classical opiates and the ORL1-N/OFQ system has pharmacological actions distinct from the opioid receptor system. This new ligand-receptor system has generated active interest in the opioid community because of its wide distribution and involvement in a myriad of neurological pathways. The past two years have witnessed tremendous advances in the design and discovery of very potent and selective peptide and nonpeptide agonist and antagonist ligands at ORL1. These discoveries have facilitated the understanding of the role of the ORL1-N/OFQ system in a variety of processes such as pain modulation, anxiety, food intake, learning, memory, neurotransmitter release, reward pathways, and tolerance development. The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction. Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics. This review presents an overview of the various peptide and nonpeptide ORL1 ligands with an emphasis on their potential therapeutic utility in various human disorders.

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“…109 From the lead 57 (potent full agonist but unselective), Hoffman La Roche developed the potent and selective full agonist Ro 65-6570, showing anxiolytic properties in rats. 142,143 Other analogues were obtained by Roche by the variation of the lipophilic substituent on the piperidine nitrogen, as 58, 142 59 144 and Ro 64-6198. 145 Currently, the latter is the nonpeptidic NOP agonist most extensively used in pharmacological and preclinical studies.…”

Section: Spiropiperidines and Spironortropanesmentioning

confidence: 99%

Development of nociceptin receptor (NOP) agonists and antagonists

Mustazza

Bastanzio

2011

Medicinal Research Reviews

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The nociceptin opioid (NOP) receptor is the most recently discovered member of the family of the opioid receptors; its endogenous agonist is the peptide nociceptin. Due to the subsequent elucidation of its physiological role in both central and peripheral nervous system and in some non-neural tissues, there is a rapidly growing interest in the pharmacological application of substances active on this receptor. Despite the current clinical use of a morphinane-based NOP/MOP mixed ligand (buprenorphine) as an analgesic and in the treatment of drug addictions, so far just a few clinical trials have been made with selective NOP ligands. However, the perspective of their utilization is rapidly growing. Agonists can find applications in the treatment of neuropathic pain, anxiety, cough, drug addition, urinary incontinence, anorexia, congestive heart failure, hypertension; and antagonists for pain, depression, Parkinson's disease, obesity, and as memory enhancers. Besides peptide ligands, which are still subjected to many pharmacological investigations, many different chemical classes of NOP ligands have been discovered: piperidines, nortropanes, spiropiperidines, 4-amino-quinolines and quinazolines, and others. The new advances in establishing structure-activity relationships, also with the help of modeling studies, can permit the development of more active and selective molecules.

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8-Acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists

Cited by 57 publications

References 12 publications

The ORL<sub>1</sub> Receptor: Molecular Pharmacology and Signalling Mechanisms

The ORL<sub>1</sub> Receptor: Molecular Pharmacology and Signalling Mechanisms

Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: Research tools and potential therapeutic agents

Development of nociceptin receptor (NOP) agonists and antagonists

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