Synthesis and analgesic effects of novel 2-tryptophan hexapeptide analogs

Adriana Bocheva (1) , Hristina Nocheva (1) , Nikola Pavlov (2) , Petar Todorov (2) , Monique Calmes (3) , Jean Martinez (3) , Emilia Naydenova (2)

1 Department of Pathophysiology
2 Department of Organic Chemistry
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

Aiming to develop more potent analgesic substances a new series of hexapeptides containing b2-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys- NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PPand HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists--naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with b2-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.

Mots clés: Nociceptin analogue NOP receptor SPPS b-Tryptophan analogues Nociception PP-test HP-latency

Domaines: Chimie organique

Adriana Bocheva, Hristina Nocheva, Nikola Pavlov, Petar Todorov, Monique Calmes, et al.. Synthesis and analgesic effects of novel 2-tryptophan hexapeptide analogs. Amino Acids, 2013, 45, pp.983-988. ⟨10.1007/s00726-013-1555-4⟩. ⟨hal-00969128⟩