Oxytocin analogues with inhibitory properties, containing in position 2 a hydrophobic amino acid of D-configuration

Abstract

Ten analogues derived from oxytocin, deamino-oxytocin and deamino-carba-oxytocin were prepared which contained a D-amino acid in the position 2 of the parent system. The following D-amino acids were introduced: tyrosine, phenylalanine, p-methylphenylalanine, p-ethylphenylalanine and O-ethyltyrosine. Combination of two structural features which alone lead to strong inhibitors (a suitable D-amino acid in position 2 and a penicillamine moiety in position 1) did not enhance the inhibitory effect. Compounds containing D-tyrosine are weak agonists in the uterotonic assay; in case of 1-carba-analogues they can be converted into sulfoxides with low inhibitory activity. Analogues with D-phenylalanine substituted in the para-position are the most potent antagonists of the uterotonic effect of oxytocin (pA2 = 8.73) in vitro.

Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations

“…The use of D-amino acids to stabilize or promote reverse turn conformations also has been widely applied in peptide design including the development of LHRH agonists and antagonists 131,32], substance P antagonists [33], oxytocin antagonists [34,35], melanotropin superagonists [36], enkephalin agonists [37], som-atostatin analogues [11,38] and others. D-Amino acid residues also can help stabilize a peptide from enzymic degradation.…”

Substitution of the Side-Chain-Constrained Amino Acids β-Methyl-2‘,6‘-Dimethyl-4‘-Methoxytyrosine in Position 2 of a Bicyclic Oxytocin Analogue Provides Unique Insights into the Bioactive Topography of Oxytocin Antagonists

“…The biological activity data are highly consistent with the binding affinities to the uterine OT receptor. Both l - and d -aromatic amino acids in position 2 of oxytocin are known to produce potent OT antagonists, and methylation of the 4‘-hydroxyl group of Tyr 2 increases the antagonistic potency . Therefore, the high antagonistic potency of two analogues with opposite chiralities at C α in position 2 is not surprising.…”

Synthesis of methylated phenylalanines via hydrogenolysis of corresponding 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acids

“…The second part was cyclized again with formaldehyde in the Pictet-Spengler manner, thus affording 5-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (MeTic). This compound, which is also potentially use- uterotonic inhibitor (13)(14)(15)). (For a discussion of very extensive research in this area see e.g.…”

“…Solid-phase peptide syntheses were performed on semiautomatic apparatus of our own construction (Institute for Organic Chemistry and Biochemistry, Prague, Czech Republic). The progress of each coupling step was followed by the ninhydrin (12) and bromophe-no1 blue (13) tests. In the case of coupling on the secondary amino group of proline the chloranil test was used.…”