ABSTRACT
The heptadecapeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor) and is involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents overview of the several recently reported NOP ligands (agonists and antagonists), with an emphasis of the structural features that may be important for modulating the intrinsic activity of these ligands. In addition, a brief account on the characterization of newly synthesized ligands of NOP receptor with aminophosphonate moiety and ß-tryptophan analogues will be presented.
Subject(s)
Analgesics, Opioid/pharmacology , Drug Design , Narcotic Antagonists/pharmacology , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Peptides/pharmacology , Receptors, Opioid/metabolism , Analgesics, Opioid/chemistry , Analgesics, Opioid/metabolism , Animals , Drugs, Investigational/chemistry , Drugs, Investigational/metabolism , Drugs, Investigational/pharmacology , Humans , Ligands , Molecular Structure , Narcotic Antagonists/chemistry , Narcotic Antagonists/metabolism , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Neurons/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Oligopeptides/pharmacology , Opioid Peptides/chemistry , Opioid Peptides/metabolism , Opioid Peptides/pharmacology , Peptides/chemistry , Peptides/metabolism , Receptors, Opioid/agonists , Receptors, Opioid/chemistry , Receptors, Opioid/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Nociceptin Receptor , NociceptinABSTRACT
New series of N-modified analogues of the N/OFQ(1-13)NH(2) with aminophosphonate moiety have been synthesized and investigated for biological activity. These peptides were prepared by solid-phase peptide synthesis-Fmoc-strategy. The N/OFQ(1-13)NH(2) analogues were tested for agonistic activity in vitro on electrically stimulated rat vas deferens smooth-muscle preparations isolated from Wistar albino rats. Our study has shown that the selectivity of the peptides containing 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids to the N-side of Phe is not changed-they remain selective agonists of NOP receptors. The derivative with the largest ring (NOC-6) demonstrated efficacy similar to that of N/OFQ(1-13)NH(2), but in a 10-fold higher concentration. The agonistic activity of newly synthesized N-modified analogues of N/OFQ(1-13)NH(2) with aminophosphonate moiety was investigated for the first time.
Subject(s)
Opioid Peptides/pharmacology , Organophosphonates/pharmacology , Peptide Fragments/pharmacology , Receptors, Opioid/agonists , Amino Acid Sequence , Animals , Electric Stimulation , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Opioid Peptides/chemical synthesis , Organophosphonates/chemical synthesis , Peptide Fragments/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Vas Deferens/drug effects , Vas Deferens/physiology , Nociceptin Receptor , NociceptinABSTRACT
The present study aimed to investigate the effects of pentoxifylline (PTX) on the carrageenan (CG)-induced paw oedema and on the endogenous levels of cell enzyme and non-enzyme antioxidants in rat liver, 4 and 24 h after CG injection. PTX (50 mg kg(-1) , i.p.), administered 30 min before CG, decreased the paw oedema, 2-4 h after CG administration. The drug protected CG-induced decrease of glutathione (non-enzyme antioxidant) and had no effect on CG-unchanged activities of superoxide dismutase, glutathione peroxidase (enzyme antioxidants) and glucose-6-phosphate dehydrogenase (enzyme, important for the activity of GSH-conjugated antioxidant enzymes). The drug showed a good antioxidant capacity in chemical systems, generating reactive oxygen species. The present results suggest that the antioxidant activity of PTX might contribute to its beneficial effects in liver injuries.
Subject(s)
Antioxidants/pharmacology , Edema/metabolism , Liver/drug effects , Pentoxifylline/pharmacology , Animals , Carrageenan , Edema/chemically induced , Edema/drug therapy , Free Radical Scavengers , Hindlimb , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Liver/metabolism , Male , Rats , Rats, WistarABSTRACT
The aim of the present study was the synthesis and the biological screening of new analogs of Ac-RYYRWK-NH2, modified at the N-terminal with 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids. The four newly synthesized ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) have been prepared by solid-phase peptide synthesis--Fmoc-strategy. These compounds were tested for agonistic activity in vitro on electrically stimulated smooth-muscle preparations isolated from vas deferens of Wistar rats. Our data showed that substitution of Arg at position 1 with aminophosphonates moiety decreased significantly the affinity of ligands to the NOP receptor. Furthermore, the enlargement of the cycle (with 5-8 carbon atoms) additionally diminished both the activity and the selectivity for NOP-receptor.
Subject(s)
Muscle, Smooth/drug effects , Organophosphonates/chemistry , Peptides/chemical synthesis , Peptides/pharmacology , Receptors, Opioid/metabolism , Vas Deferens/drug effects , Animals , Electric Stimulation , Ligands , Male , Molecular Structure , Molecular Weight , Muscle, Smooth/physiology , Peptides/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Vas Deferens/physiology , Nociceptin ReceptorABSTRACT
The purpose of the present study was the synthesis and the biological screening of new analogues of N/OFQ(1-13)NH2, the minimal sequence maintaining the same activity as the natural peptide nociceptin. In order to investigate the role of Lys, we substituted Lys at positions 9 and/or 13 by Orn, Dab (diaminobutanoic acid) or Dap (diaminopropanoic acid). The new N/OFQ(1-13)NH2 analogues exerted strong and naloxone-resistant inhibition of electrically evoked contractions of rat vas deferens. Lys replacement with Orn maintained or even enhanced the inhibitory activity, while replacements with Dab and Dap decreased inhibitory activity.
