RESUMO
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.
Assuntos
Peptídeos Opioides/farmacologia , Organofosfonatos/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores Opioides/agonistas , Sequência de Aminoácidos , Animais , Estimulação Elétrica , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Peptídeos Opioides/síntese química , Organofosfonatos/síntese química , Fragmentos de Peptídeos/síntese química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologia , Receptor de Nociceptina , NociceptinaRESUMO
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.
Assuntos
Músculo Liso/efeitos dos fármacos , Organofosfonatos/química , Peptídeos/síntese química , Peptídeos/farmacologia , Receptores Opioides/metabolismo , Ducto Deferente/efeitos dos fármacos , Animais , Estimulação Elétrica , Ligantes , Masculino , Estrutura Molecular , Peso Molecular , Músculo Liso/fisiologia , Peptídeos/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Ducto Deferente/fisiologia , Receptor de NociceptinaRESUMO
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.