Des agonistes puissants et sélectifs des récepteurs d'ocytocine sans ponts disulfure

Aperçu: G.M.

L'oxytocine (OT) est un neuropeptide impliqué dans une grande variété d'actions physiologiques. 

De nombreuses études sur l'homme ont révélé le potentiel de l'OT pour traiter les troubles du spectre de l'autisme.

OT interagit avec le récepteur OT (OTR) ainsi que les récepteurs vasopressine 1a et 1b (V1aR, V1bR) comme agoniste, et l'activité agoniste pour V1aR et V1bR peut avoir un impact négatif sur les effets thérapeutiques de l'agonisme OTR dans le SNC. 

Les chercheurs ont étudié une modification complète de l'AT et obtenu de nouveaux analogues de l'OT qui présentaient une forte puissance à l'OTR avec une sélectivité marquée. Ces agonistes sélectifs d'OTR pourraient être utiles pour enquêter sur les effets médiés par l'OTR sur les troubles  

Bioorg Med Chem Lett. 2017 Apr 12. pii: S0960-894X(17)30406-7. doi: 10.1016/j.bmcl.2017.04.030

Potent and selective oxytocin receptor agonists without disulfide bridges

Adachi Y¹, Sakimura K¹, Shimizu Y¹, Nakayama M¹, Terao Y¹, Yano T¹, Asami T².

Author information

1

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.

2

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan. Electronic address: taiji.asami@takeda.com

Abstract

Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V_1aR, V_1bR) as an agonist, and agonistic activity for V_1aR and V_1bR may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, V_1aR, and V_1bR activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp⁷,Leu(Me)⁸]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over V_1aR and V_1bR. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders.

Copyright © 2017 Elsevier Ltd. All rights reserved.

PMID: 28438540

DOI: 10.1016/j.bmcl.2017.04.030