Design, Synthesis and Biological Evaluation of Two Opioid Agonist and Cav 2.2 Blocker Multitarget Ligands.
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.
Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100, Chieti, Italy.
Adriano
http://orcid.org/0000-0002-7242-4860
A
Mollica
Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100, Chieti, Italy.
Roberto
R
Costante
Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
Ettore
E
Novellino
Dipartimento di Chimica, Sapienza, Università di Roma, P.le A. Moro 5, 00187, Rome, Italy.
Azzurra
A
Stefanucci
Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, V.le Regina Elena 299, 00161, Rome, Italy.
Stefano
S
Pieretti
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726, Szeged, Hungary.
Ferenc
F
Zador
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726, Szeged, Hungary.
Reza
R
Samavati
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726, Szeged, Hungary.
Anna
A
Borsodi
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726, Szeged, Hungary.
Sándor
S
Benyhe
Institute for Molecular Bioscience, The University of Queensland, Brisbane St Lucia, Qld 4072, Australia.
Irina
I
Vetter
Institute for Molecular Bioscience, The University of Queensland, Brisbane St Lucia, Qld 4072, Australia.
Richard J
RJ
Lewis
D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D020916:Conotoxins / Q000737:chemistry; D015195:Drug Design; D008024:Ligands; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D020960:omega-Conotoxins / Q000737:chemistry / Q000494:pharmacology
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020916:Conotoxins; D008024:Ligands; D009842:Oligopeptides; D020960:omega-Conotoxins; C038614:tyrosyl-alanyl-glycyl-phenylalanine
CaV2.2; analgesic; conotoxin; multitarget ligands; opioid; pain