(8‐Naphthalen‐1‐ylmethyl‐4‐oxo‐1‐phenyl‐1,3,8‐triaza‐spiro[4.5]dec‐3‐yl)‐acetic acid methyl ester (NNC 63‐0532) is a novel potent nociceptin receptor agonist

Thomsen, C.; Hohlweg, Rolf

doi:10.1038/sj.bjp.0703661

Cited by 38 publications

(31 citation statements)

References 17 publications

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“…Ro 64-6198 at high concentrations could act at dopamine D 2 receptors and opioid receptors (Dautzenberg et al, 2001;Rizzi et al, 2001). Besides, the structure of Ro 64-6198 is similar to the 5-HT 1A agonist, spiroxatrine (Herrick-Davis and Titeler, 1988), from which a nonpeptide NOP receptor agonist, NNC 63-0532, has been developed (Thomsen and Hohlweg, 2000). We further examined if sulpiride, naloxone, and NAN-190, the antagonists of dopamine D 2 , opioid, and 5-HT 1A receptors, respectively, would reverse the effect of Ro 64-6198.…”

Section: Resultsmentioning

confidence: 99%

Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] Acts Differently from Nociceptin/Orphanin FQ in Rat Periaqueductal Gray Slices

Chiou

Chuang²,

Wichmann³

et al. 2004

J Pharmacol Exp Ther

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3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] was developed as a nonpeptide agonist of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, using bioassays at cloned receptors expressed in cell cultures. We have investigated the actions of Ro 64-6198 at native NOP receptors of the ventrolateral periaqueductal gray (PAG), a crucial site for N/OFQ-induced reversal of opioid analgesia, using the patch-clamp recording technique in rat brain slices. Ro 64-6198, like N/OFQ, activated G protein-coupled inwardly rectifying K ϩ channels (GIRK) in ventrolateral PAG neurons but displayed only 60% efficacy and 22% potency of N/OFQ. Unlike N/OFQ that activated GIRK through NOP receptors in almost all tested neurons, Ro 64-6198 affected only 62% (114/185) of the neurons recorded, among which 57% were sensitive to CompB (J-113397), a selective NOP receptor antagonist. The effect of Ro 64-6198 was not affected by naloxone (1 M), sulpiride (10 M), and [1-(2-methoxyphenyl)-4-[4-2-phthalimido)butyl]piperazine (1 M), respectively, the antagonist of opioid, dopamine D 2 , and 5-HT 1A receptors. In Ro 64-6198-unresponsive neurons, N/OFQ activated GIRK through NOP receptors. It is concluded that Ro 64-6198 is a weak agonist of NOP receptors both in terms of potency and efficacy in ventrolateral PAG neurons. Heterogeneity of NOP receptors has been proposed from binding studies and in vivo functional studies. The possibility was discussed that two subsets of NOP receptors exist in ventrolateral PAG neurons, and Ro 64-6198 activates only one subset but N/OFQ activates both of them.

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Section: Resultsmentioning

confidence: 99%

Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] Acts Differently from Nociceptin/Orphanin FQ in Rat Periaqueductal Gray Slices

Chiou

Chuang²,

Wichmann³

et al. 2004

J Pharmacol Exp Ther

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“…The several small-molecule ORL1 receptor ligands recently reported in the literature, such as J-113397 (Kawamoto et al, 1999), Ro 64-6198 , and NNC 63-0532 (Thomsen and Hohlweg, 2000), were developed from screening leads that bear close structural resemblance to well-known piperidine-containing neuroleptics and opiate ligands. Their ORL1 affinity was primarily increased through modification of the N-1 piperidine substituent (Kawamoto et al, 1999;Rover et al, 2000;Thomsen and Hohlweg, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Their ORL1 affinity was primarily increased through modification of the N-1 piperidine substituent (Kawamoto et al, 1999;Rover et al, 2000;Thomsen and Hohlweg, 2000). Most of the known neuroleptics as well as the anilidopiperidine class of opiates possess the Nphenethyl, or a similar extended alkyl chain bearing an aromatic ring, at the N-1 of the piperidine (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…The group from Banyu described a high affinity and selective ORL1 receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397), obtained by extensive modification of a lead compound identified by screening (Kawamoto et al, 1999;Ozaki et al, 2000). High affinity agonists, on the other hand, were reported by Hoffman La Roche (Wichmann et al, 1999;Rover et al, 2000) and Novo Nordisk (Thomsen and Hohlweg, 2000). The Roche compound, (1S,3aS)-8-(2,3,3a, 4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (Ro 64-6198), is a potent agonist at ORL1(K i = 0.39 nM) and has >100-fold selectivity over the opioid receptors.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Zaveri

Polgar

Olsen

et al. 2001

European Journal of Pharmacology

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Nociceptin/orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioidreceptor like (ORL1) receptor. Although the ORL1 receptor shows sequence homology with the opioid receptors, the nociceptin/ORL1 ligand-receptor system has very distinct pharmacological actions compared to the opioid receptor system. Recently, several small-molecule ORL1 receptor ligands were reported by pharmaceutical companies. Most of these ligands had close structural similarities with known neuroleptics and opiates. In this study, we screened several available neuroleptics and opiates for their binding affinity and functional activity at ORL1 and the opioid receptors. We also synthesized several analogs of known opiates with modified piperidine Nsubstituents in order to characterize the ORL1 receptor ligand binding pocket. Substitution with the large, lipophilic cyclooctylmethyl moiety increased ORL1 receptor affinity and decreased μ receptor affinity and efficacy in the fentanyl series of ligands but had a different effect in the oripavine class of opiate ligands. Our results indicate that opiates and neuroleptics may be good starting points for ORL1 receptor ligand design, and the selectivity may be modulated by appropriate structural modifications.

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“…21 Similar approaches have been used to develop other small-molecule NOP agonists and antagonists like Ro 64-6198, NNC 63-0532, and JTC-801. 20,23,24 At present, high-throughput screening coupled with classical medicinal chemistry is still the most common strategy for identification and development of small molecule NOP agonists or antagonists. The discovery of these selective NOP agonist and antagonists has afforded a considerable opportunity to develop a high affinity binding pharmacophore for the NOP receptor, which can be used to accelerate future drug discovery.…”

mentioning

confidence: 99%

The design and synthesis of a novel quinolizidine template for potent opioid and opioid receptor-like (ORL1, NOP) receptor ligands

Jong

Zaveri

Toll

2004

Bioorganic & Medicinal Chemistry Letters

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A new class of high affinity opioid and opioid receptor-like receptor (ORL1 receptor, NOP receptor) ligands has been designed by conformational restriction of piperidine-based NOP receptor ligands, resulting in a novel quinolizidine scaffold. Different modifications of the pendant functional groups on the scaffold provide differential activities at the opioid and NOP receptors. While the conformational rigidity will provide an improved understanding of the NOP and opioid receptor binding pockets, these compounds also provide a new template for the design of novel opiate and NOP ligands.Nociceptin (NC, Orphanin FQ (N/OFQ)) is the endogenous ligand for the opioid receptorlike (ORL1) receptor (now called the NOP receptor). 1,2 Although NOP/ORL1 is a member of the opioid receptor family, and is a G-protein coupled receptor, it does not bind opiates with high affinity. The NOP receptor and nociceptin have been implicated in several physiological pathways including pain, anxiety, and drug addiction. 3,4 A variety of studies have suggested that NOP agonists may be useful clinically for treatment of anxiety, 5 and antagonists may have analgesic activity. [6][7][8] In addition, various pharmacological and genetic manipulations have indicated that this receptor and N/OFQ may also be involved in morphine tolerance, 9 feeding, 10 learning and memory, 11,12 cardiovascular and renal systems, 13,14 among others. Therefore, development of highly selective and potent NOP ligands could provide new classes of drugs for several human disorders.Since nociceptin is a 17-amino acid peptide, several earlier studies have resulted in the identification of modified N/OFQ-based peptide ligands for the NOP receptor (reviewed in ref 15). Very selective peptide agonists as well as antagonists have now been identified. [16][17][18] However, despite this enhanced understanding of the structural requirements of N/OFQ-like peptides, the information is not sufficient to support rational small-molecule NOP ligand design. Furthermore, the use of peptide ligands is plagued with inherent limitations with respect to metabolic stability.Recently, several small-molecule NOP agonists and antagonists have been reported in the literature 19-25 and patents (reviewed in ref 15). Several of these ligands possess very high selectivity for the NOP receptor versus other opioid receptors. For example, Kolczewski et al. recently reported novel spiropiperidine-based pyrrolo-pyrroles, of which compound 1 (Fig. 1) was identified as a potent NOP agonist (K i =0.49 nM) with >1000-fold selectivity over the μ, δ, and κ opioid receptors. 25 It is interesting to note that all small-molecule NOP ligands disclosed thus far contain a common piperidine core and bear close structural resemblance to lofentanil and the anilidopiperidine class of opioid ligands. 26 Most of these reported ligands were discovered through high throughput screening of large libraries and the resulting hits were optimized for potency and selectivity versus other opioid receptors by modifying th...

show abstract

(8‐Naphthalen‐1‐ylmethyl‐4‐oxo‐1‐phenyl‐1,3,8‐triaza‐spiro[4.5]dec‐3‐yl)‐acetic acid methyl ester (NNC 63‐0532) is a novel potent nociceptin receptor agonist

Cited by 38 publications

References 17 publications

Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] Acts Differently from Nociceptin/Orphanin FQ in Rat Periaqueductal Gray Slices

Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] Acts Differently from Nociceptin/Orphanin FQ in Rat Periaqueductal Gray Slices

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

The design and synthesis of a novel quinolizidine template for potent opioid and opioid receptor-like (ORL1, NOP) receptor ligands

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