Synthesis of partial nonpeptidic peptide mimetics as potential neurotensin agonists and antagonists

Alan P. Kozikowski, Dharmpal S. Dodd, Javid Zaidi, Yuan Ping Pang, Bernadette Cusack, Elliott Richelson

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The synthesis of partially nonpeptidic peptides as mimetics of neurotensin (8-13) [NT(8-13)] is described. The sequence Arg8Arg 9Pro10 of NT(8-13) was replaced by substituted indole-2-carboxylates as non-peptidic equivalents. For the NT(8-13) fragment, a range of dimensions was calculated with the aid of computer modelling of which a subset was translated synthetically into two structures (1 and 2) containing indole-2-carboxylates substituted with guanidines containing appendages at C-3/C-5 and C-3/C-7, respectively. Regioisomeric C-5 and C-7 substituted indole intermediates 4 and 5 were obtained from a single indole precursor 3 via thermally induced nitrene insertion. The readily separable indoles 4 and 5 were isolated as a ∼ 1:1 mixture. In turn, these indoles were functionalized individually in seven steps to give the Pmc-protected bisguanidino indole-2-carboxylic acids 14a and 14b, respectively. The carboxylic acids were coupled to the resin-bound tripeptide fragment NT(11-13), and the resulting products were cleaved from the resin using a trifluoroacetic acid cocktail to give NT mimetics 1 and 2. Functional evaluation of 1 and 2 on neuroblastoma N1E-115 cells showed mimetic 1 to be an NT antagonist, while mimetic 2 was found to be an NT antagonist at low concentrations and an NT agonist at higher concentrations in the 10-100 μmol dm-3 range.

Original languageEnglish (US)
Pages (from-to)1615-1621
Number of pages7
JournalJournal of the Chemical Society, Perkin Transactions 1
Issue number12
DOIs
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Chemistry(all)

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