Introduction of a cis-prolyl mimic in position 7 of the peptide hormone oxytocin does not result in antagonistic activity.
ABSTRACT New insights into the structure-activity relationship of the peptide hormone oxytocin are presented. Incorporation of the novel cis-prolyl mimic 2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid (pseudoproline, PsiPro) at position 7 of the hormone yielded the analogue [Cys(Psi(Me,Me)pro)]7oxytocin (1) that showed a 92-95% induction of the cis peptide bond conformation between Cys6 and PsiPro7, as determined by one- and two-dimensional NMR spectra in water and in DMSO-d6. The impact of the dimethyl moiety regarding conformation and bioactivity was investigated by the synthesis of the corresponding dihydro compound, [Cys(Psi(H,H)pro)]7oxytocin (2). Biological tests of the uterotonic activity, the pressor activity, and the binding affinity to the rat and human oxytocin receptors were carried out. As a most significant result, no antagonistic activities were found for both the cis-constrained analogue 1 and analogue 2, suggesting that a cis conformation between residues 6 and 7 of the molecule does not result in antagonistic activity. However, the about 10-fold reduction in agonistic activity of 1 as compared to oxytocin is consistent with the reduction of the trans conformation from 90% for oxytocin to 5-8% for compound 1. Compound 1 retained a high binding affinity for the oxytocin receptor, with K(i) values of 8.0 and 1.9 nM for the rat and the human receptor, respectively. The correlation between the biological activities and the cis contents obtained from NMR analysis for compounds 1, 2, and oxytocin leads to the hypothesis that a cis/trans conformational change plays an important role in oxytocin receptor binding and activation.
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ABSTRACT: The reaction of thioamino acids and N-terminal peptides, mediated by hindered isonitriles and hydroxybenzotriazole, gives rise to peptide bonds. In one pathway, oxytocin was synthesized by eight such reiterative amidations. In another stereospecific track, oxytocin was constructed by native chemical ligation, wherein the two building blocks were assembled by thioacid amine amidation. The NMR spectra of oxytocin and dihydrooxytocin suggest a high level of preorganization in the latter, perhaps favoring oxidative folding.Journal of the American Chemical Society 07/2012; 134(32):13244-7. · 10.68 Impact Factor
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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-ThiMeGly7]dOT), 47 (carba-6-[Phe2,BuGly7]dOT), 55 (carba-6-[3-MeBzlGly7]dOT) and 57 (carba-1-[4-FBzlGly7]dOT) have EC50 values at the hOTR < 0.1 nM, selectivity ratios versus related human vasopressin receptors > 2000, IC50 at hV1aR > 500 nM, and total clearance in rats in the range of 60-80 mL/min/kg. Compound 57 (FE 202767) is currently in clinical development for the treatment of preterm mothers requiring lactation support.Journal of Medicinal Chemistry 05/2014; 57:5306-5317. · 5.61 Impact Factor
- Australian Journal of Chemistry 01/2010; 63(5). · 1.87 Impact Factor