Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

Abstract

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3’,5’-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioral assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

“…19,20,26 Moreover, the in vivo studies showed activity in acute pain 26 as well as in neuropathic pain models. 20 The potent analgesic responses after intravenous (i.v.)…”

“…19,20,26 Moreover, the in vivo studies showed activity in acute pain 26 as well as in neuropathic pain models. 20 The potent analgesic responses after intravenous (i.v.) administration indicated that these hybrid compounds were capable of crossing the blood−brain barrier (BBB), but unfortunately they still produced analgesic tolerance and cross-tolerance with morphine.…”

“…administration indicated that these hybrid compounds were capable of crossing the blood−brain barrier (BBB), but unfortunately they still produced analgesic tolerance and cross-tolerance with morphine. 20,26 The activity profile of DMLs, such as the opioid agonist-NK1 antagonist hybrids, is often dependent on the relative potency at the two target receptors, the modulation of which is a very challenging aspect of DML design.…”

“…20 Both compounds belong to the subclass of "merged" DMLs, in which the two pharmacophores, interacting with two different targets, overlap ( Figure 1). The opioid agonist part is derived from the μ opioid receptor agonist Dmt-D-Arg-Phe-Lys-NH 2 …”

“…The Boc-Dmt-D-Arg(Pbf)-AbaβAla-OH peptide, precursor of compounds 12−14, was prepared by direct assembly of the Aba scaffold on the solid support following a protocol recently described. 20 The coupling of Boc-Dmt-OH was performed using 3 equiv of DIC/3 equiv of HOBt as the coupling mixture to avoid side reactions that occur when uronium reagents (e.g., TBTU/DIPEA) are used. The fully protected tetrapeptides were cleaved from the resin using a mixture of 1% TFA in DCM for 1 h. The protected peptide acids were coupled to the secondary amines (1.5 equiv of amines 4−6) using 1.5 equiv of DIC/1.5 equiv of HOBt (for 4 and 6) or HOAt (for 5) in DCM at room temperature.…”