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Design,Synthesis and Biological Evaluation of Two Opioid Agonist and Cav2.2 Blocker Multitarget Ligands |
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| Authors: | Adriano Mollica Roberto Costante Ettore Novellino Azzurra Stefanucci Stefano Pieretti Ferenc Zador Reza Samavati Anna Borsodi Sándor Benyhe Irina Vetter Richard J. Lewis |
| Affiliation: | 1. Dipartimento di Farmacia, Università di Chieti‐Pescara “G. d'Annunzio”, Chieti, Italy;2. Dipartimento di Farmacia, Università di Napoli “Federico II”, Naples, Italy;3. Dipartimento di Chimica, Sapienza, Università di Roma, Rome, Italy;4. Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy;5. Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary;6. Institute for Molecular Bioscience, The University of Queensland, Brisbane St Lucia, Qld 4072, Australia |
| Abstract: | N‐type voltage‐dependent Ca2+ channels (CaV2.2) 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. CaV2.2 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 CaV2.2 and opioid receptors and no significant synergistic activity. |
| Keywords: | analgesic CaV2.2 conotoxin multitarget ligands opioid pain |