Design, Synthesis and Biological Evaluation of Two Opioid Agonist and Ca_v2.2 Blocker Multitarget Ligands

Abstract

N-type voltage-dependent Ca(2+) channels (CaV 2.2) are located at nerve endings in the central and peripheral nervous systems and are strongly associated with the pathological processes of cerebral ischaemia and neuropathic pain. CaV 2.2 blockers such as the ω-conotoxin MVIIA (Prialt) are analgesic and have opioid-sparing effects. With the aim to develop new multitarget analgesic compounds, we designed the first ω-conotoxin/opioid peptidomimetics based on the enkephalin-like sequence Tyr-D-Ala-Gly-Phe (for the opioid portion) and two fragments derived from the loop-2 pharmacophore of ω-conotoxin MVIIA. Antinociceptive activity evaluated in vitro and in vivo revealed differential affinity for CaV 2.2 and opioid receptors and no significant synergistic activity.

Design, synthesis and biological profile of mixed opioid agonist/N-VGCC blocker peptides

“…administration. A close comparison of the analgesic effect can be done with the previously synthetized multi-target compound 10 reported by Mollica et al 16 (Figure 1 and 4).…”

“…However, the design was not entirely satisfactory since the potency of the pharmacophore blocking the VGCC channels was significantly lower than that of the opioid portion. 16 In this study we have designed our novel bi-functional molecules by following different approaches showed schematically in Figure 2 described by Hu et al 17 aimed to introduce an N-terminus group suitable for coupling to the opioid pharmacophore. It is worth noting that this modified fragment is 1000 times more active than the pharmacophore used in our previous design (Ser-Arg-Leu-Met-Tyr-NH 2; EC 50 = 80µM) 16 ( Figure 1).…”

“…Peptide elongation was performed following the procedure previously described until to reach the complete sequence. 16 Isolation of the intermediates was performed on silica gel chromatography. Final products 5-9 were obtained as TFA salts and purified in RP-HPLC following the procedure described in Methods.…”

Emerging biopharmaceuticals from bioactive peptides derived from marine organisms

“…Traditionally, the first option to be explored for the supply of marine‐derived small biomolecules is chemical synthesis, thanks to the improved synthesis techniques and medicinal chemists who made it possible to some extent . One successful example of the synthetic production of a marine‐derived drug in extensive quantities is the conus toxin ziconotide, because of its peptide nature .…”

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

“…Some of the representative heterodimers include ΜOR/DOR, 2 ΜOR/ΚOR, 4 ΜOR/cannabinoid receptor type 1, 5 ΜOR/metabotropic glutamate receptor type 5, 6 ΜOR/chemokine-receptor type 5, 7 ΜOR/NSAIDs 8 and ΜOR/N-type Ca 2+ channels. 9 It is known that opioid and dopamine receptors are co-distributed in many brain tissues, indicating possible functional interaction. 10,11 Thus, there is significant evidence of opioid-dopaminergic cross regulation, especially in reward processes associated with opioid addiction.…”