New, Potent, and Selective Peptidic Oxytocin Receptor Agonists

Abstract

Mothers of preterm babies frequently have difficulty establishing or maintaining lactation, thought to be due to interference with the milk ejection reflex. Administration of exogenous oxytocin can produce alveolar contraction and adequate breast emptying resulting in establishment of successful lactation. The natural hormone oxytocin is not receptor-selective and may cause hyponatremia via V2 receptor mediated antidiuresis. We have designed a series of potent oxytocin analogues containing N-alkylglycines in position 7 with excellent selectivity versus the related V1a, V1b, and V2 vasopressin receptors and short half-life: agonists 31 ([2-ThiMeGly(7)]dOT), 47 (carba-6-[Phe(2),BuGly(7)]dOT), 55 (carba-6-[3-MeBzlGly(7)]dOT), and 57 (carba-1-[4-FBzlGly(7)]dOT) have EC50 values at hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors of >2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL min(-1) kg(-1). Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support.

Carbetocin is a Functional Selective Gq Agonist That Does Not Promote Oxytocin Receptor Recycling After Inducing β‐Arrestin‐Independent Internalisation

“…Interestingly, our data for V1bR confirmed the results of the previous study (35) that used an in vitro luciferase-based transcription reporter gene assay and reported no activation of this receptor by carbetocin at a concentration up to 10 lM. However, in contrast to the present study, a partial agonism for V1aR, arbitrarily assigned to < 70%, was reported in the previous study (35). Unfortunately, we cannot make direct comparisons between our BRET studies and the previous studies because, in the latter case, the nature of the responsive elements present in the promoter of their construct was not described, and we cannot therefore establish with certainty which signalling pathway was activated by the peptide.…”

“…Moreover, the neuropeptide arginine vasopressin significantly promoted the coupling/activation of the vasopressin V1aR and V1bR to all G-protein subtypes. Interestingly, our data for V1bR confirmed the results of the previous study (35) that used an in vitro luciferase-based transcription reporter gene assay and reported no activation of this receptor by carbetocin at a concentration up to 10 lM. However, in contrast to the present study, a partial agonism for V1aR, arbitrarily assigned to < 70%, was reported in the previous study (35).…”

“…Moreover, we observed that it can act as a competitive antagonist at the vasopressin receptors. This is an important feature that differentiates carbetocin from oxytocin because oxytocin is capable to bind to and activate both the V1a and V1b receptors . Previously, a great deal of effort was devoted to the identification of OXTR selective antagonists and, more recently, interest in OXTR selective agonists has surged.…”

Cysteine-, Methionine- and Seleno-Cysteine-Proline Chimeras: Synthesis and Their Use in Peptidomimetics Design

“…The most important synthetic strategies reported in literature to prepare these chimeric compounds have been reported and discussed. They are particularly important in peptidomimetics design; for example, Wi niewski reported a small library of oxytocin analogues [36], which show selectivity to vasopressin receptors and present several chemical modification, including the introduction of trans-4-SMe-Pro residue in peptide 57 (Fig. 4).…”

“…Synthesis of bis -amino acids from 4-hydroxylproline by Caputo et al[34]. An oxytocin analog containing a Met-Pro chimera residue[36].…”