Isolation of RP 66453, a New Secondary Peptide Metabolite from Streptomyces sp. Useful as a Lead for Neurotensin Antagonists.

Abstract

The tridecapeptide neurotensine has been the subject of increased interest since its discovery and characterization in the brain1). Aspects of its pharmacology include physiological effects both in the periphery and the central nervous system2). In order to elucidate further its pathophysiological role, neurotensin agonists and antagonists are needed.In the course of our screening program to find substances that displace the neurotensin from its receptor, a receptor binding assay using guinea-pig brain membranes was performed according to GOEDERT et al.3

Total Synthesis of an Atropdiastereomer of RP‐66453 and Determination of Its Absolute Configuration

“…[1] This new bicyclic compound binds very selectively to the neurotensin receptor from guinea pigs (IC 50 = 30 mg mL À1 ). Subsequent structural modification has led to the discovery of potent neurotensin antagonists claimed to be useful for treating psychosis and Alzheimer's and Parkinson's diseases.…”

RA‐dimer B, a New Dimeric RA‐series Cyclopeptide Incorporating Two Different Types of Cycloisodityrosine Units, from Rubia cordifolia L.

“…The cycloisodityrosine structure incorporated in unit A, in which an ether linkagei sf ormed between the hydroxyl oxygen at the position of the N-terminal tyrosinea nd the carbon atom at the e positiono ft he C-termi- nal tyrosine, is characteristico fR A-seriesp eptidesa nd bouvardins, and that in unit B, in which an ether linkageisformedbetween the carbon atom at the e position of the N-terminal tyrosine andt he hydroxyl oxygen at the position of the C-terminal tyrosine, are seen in only allo-RA-V (5)a nd RP66453, am etabolite of a Streptomyces strain, which exhibits specific binding affinity for the neurotensin receptor. [15,16] O-Seco-deoxybouvardin (16)h as been isolated from this plant as ap ossible biosynthetic precursor of deoxybouvardin (4)a nd allo-RA-V (5). [9,17] RA-dimer B( 3)m ay be biosynthesized by oxidative couplingo f16 with 4 to produce dimeric inter-mediate 17 and the subsequento xidative formation of the diphenyle ther ring of the allo-RA-V unit of 3 (Scheme 3).…”

Bridged bicyclic peptides: Structure and function

“…A more common structural feature is a biaryl ether crosslink between two Tyr residues. RP‐66453 ( 55 ) was isolated from an Actinomycetes strain and was shown to selectively bind to the neurotensin receptor . RP‐66453 contains a cycloisodityrosine moiety, in which adjacent Tyr residues are connected through a biaryl ether cross‐link.…”