Nociceptin antagonism: probing the receptor by N-acetyl oligopeptides

Kocsis, László; Orosz, György; Magyar, Anna; Al-Khrasani, Mahmoud; Kató, Erzsébet; Rónai, A. Z.; Bes, Brice; Meunier, Jean Claude; Gündüz, Özge; Tóth, Géza; Borsodi, Anna; Benyhe, Sándor

doi:10.1016/j.regpep.2004.06.019

Cited by 20 publications

(18 citation statements)

References 48 publications

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“…35 S] binding experiments in rat brain membranes and mouse vas deferens bioassays [24] . However, subsequent in vitro and in vivo pharmacological characterization indicated that the hexapeptide alcohol is actually a low efficacy partial agonist [25] .…”

Section: Discussionmentioning

confidence: 99%

“…Fmoc-Lys(Boc)-ol [24] was synthesized from FmocLys(Boc)-OH through its mixed anhydride using sodium borohydride at 0 ° C. Fmoc-Lys(Boc)-OH was attached to Rink amide resin in DCM using DIPCI and HOBt. The protocol of the peptide synthesis was the following: (1) DMF washing (3 !…”

Section: Peptide Synthesismentioning

confidence: 99%

“…Crude brain membrane from Wistar rats was prepared as previously described [24,29] . Briefly, rats were decapitated and the brains without cerebellum were quickly removed and washed several times with chilled 50 m M Tris-HCl buffer (pH 7.4).…”

Section: Membrane Preparationmentioning

confidence: 99%

“…Moreover, a NOP selective partial agonist with high affinity, metabolic stability and in vivo duration of action was generated by addition of a polylysine sequence to the C-terminal (Ac-RYYRWK-KKKKKK-NH 2 namely ZP-120) [21][22][23] . Finally, a high affinity NOP receptor ligand with antagonist properties was prepared by substituting the C-terminal amide with an alcoholic function, resulting in Ac-RYYRIK-ol [24] . This hexapeptide alcohol was further characterized by in vitro and in vivo approaches and turned out to be a low efficacy NOP receptor agonist with high potency, selectivity of action, metabolic stability and in vivo activity [25] .…”

Section: Introductionmentioning

confidence: 99%

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In vitro Binding and Functional Studies of Ac-RYYRIK-ol and Its Derivatives, Novel Partial Agonists of the Nociceptin/Orphanin F/Q Receptor

et al. 2006

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Following the discovery of nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) and its endogenous ligand, an extensive search has started to find selective agonists and antagonists targeting this novel receptor-ligand system due to their therapeutic potentials. By the help of the combinatorial chemistry a series of hexapeptides with a general formula of Ac-RYY-R/K-W/I-R/K-NH₂ having high NOP receptor affinity and selectivity were identified. On the basis of this information we developed a number of novel compounds. The detailed structure-activity studies on the partial agonist Ac-RYYRIK-NH₂ are reported in this communication. Besides the modifications on N- and C-terminal, Arg-Cit exchange was performed on the template structure. The novel hexapeptides were analyzed in radioligand binding, functional biochemical [³⁵S]GTPγS binding assays by using membranes from rat brains and Chinese hamster ovary cells expressing human NOP receptor. The agonist/antagonist properties were also tested on in the mouse vas deferens bioassay. C-terminal modification yielded a high affinity, selective and potent NOP ligand (Ac-RYYRIK-ol) with a partial agonist property. Several analogs of this compound were synthesized. The presence of the positively charged arginine residue at the first position turned out to be crucial for the biological activity of the hexapeptide. The N-terminal modifications with various acyl groups (ClAc, pivaloyl, formyl, benzoyl, mesyl) decreased the affinity of the ligand towards the receptor and the intrinsic activity for stimulating the G-protein activation was also decreased. The structure-activity studies on the hexapeptide derivatives provided some basic information on the structural requirements for receptor binding and activation.

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Section: Discussionmentioning

confidence: 99%

Section: Peptide Synthesismentioning

confidence: 99%

Section: Membrane Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitro Binding and Functional Studies of Ac-RYYRIK-ol and Its Derivatives, Novel Partial Agonists of the Nociceptin/Orphanin F/Q Receptor

et al. 2006

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“…Moreover, the removal of the terminal amide group had almost no effect. 67 The substitution the of C-terminal amide group in 4 with a hydroxymethyl gave the partial agonist Ac-RYYRIK-ol, 68 which displayed in vivo effects in mice similar to N/OFQ. 69 Tritiated Ac-RYYRIK-ol is a radioligand for NOP endowed with high affinity and selectivity, reversibility, and biological stability.…”

Section: Other Peptidesmentioning

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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The effect of peptide length on the cleavage kinetics of 2‐chlorotrityl resin‐bound ethers

Kocsis

Ruff

Orosz

2006

Journal of Peptide Science

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Different characteristics of cleavage kinetics of resin-bound amino alcohols and their peptide derivatives were observed in acid containing protic and aprotic solvent mixtures. The hydrolysis reactions are hindered by steric crowding around the cleaving C--O bond and accelerated by the special solvation effect of CF(3)CH(2)OH on the peptide chain as well as the increase of the strength and concentration of the acid. In trifluoroacetic acid containing mixtures, trifluoroacetylation of the peptide alcohols was detected. The appearance of O-trifluoroacetyl serine and threonine derivatives is detected in cleavage mixtures containing trifluoroacetic acid in anhydrous solvent.

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Nociceptin antagonism: probing the receptor by N-acetyl oligopeptides

Cited by 20 publications

References 48 publications

In vitro Binding and Functional Studies of Ac-RYYRIK-ol and Its Derivatives, Novel Partial Agonists of the Nociceptin/Orphanin F/Q Receptor

In vitro Binding and Functional Studies of Ac-RYYRIK-ol and Its Derivatives, Novel Partial Agonists of the Nociceptin/Orphanin F/Q Receptor

Development of nociceptin receptor (NOP) agonists and antagonists

The effect of peptide length on the cleavage kinetics of 2‐chlorotrityl resin‐bound ethers

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