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Biomed Pharmacother ; 141: 111861, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34229249

RESUMEN

The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 µg/kg) and tonic (ED50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.


Asunto(s)
Analgésicos no Narcóticos/farmacología , Compuestos Macrocíclicos/farmacología , Receptores de Neurotensina/efectos de los fármacos , Analgésicos no Narcóticos/síntesis química , Analgésicos no Narcóticos/farmacocinética , Analgésicos Opioides/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Ciclización , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Sinergismo Farmacológico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Masculino , Morfina/farmacología , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especificidad por Sustrato
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