Quantitative structure-activity analyses of bufokinin and other tachykinins at bufokinin (bNK1) receptors of the small intestine of the cane toad, Bufo marinus

Lu Liu, Michael Murray, J. Michael Conlon, Elizabeth Burcher

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

The toad tachykinin, bufokinin (Lys-Pro-Arg-Pro-Asp-Gln-Phe-Tyr-Gly-Leu-Met amide; BUF), acts via tachykinin NK1-like receptors to contract the intestine of the cane toad, Bufo marinus. In this structure-activity study, we used isolated segments of toad small intestine and performed binding studies with [125I] Bolton-Hunter BUF in intestinal membranes to compare the contribution of individual amino acid residues to the potencies of 18 naturally occurring tachykinins and 13 BUF analogs. Potencies were similar (r = 0.94) in functional and binding studies, with BUF and ranakinin being most potent. Ranatachykinin A, physalaemin, hylambatin and cod, trout and mammalian SPs exhibited 10-60% of the potency of BUF. The Ala-substituted BUF analogs were 11-60% as potent as BUF in functional studies, with [Ala2]-BUF and [Ala4]-BUF the least efficacious, indicating the importance of both proline residues. QSAR equations were developed using 12 connectivity, shape and steric parameters for each of the 7 hypervariable amino acid residues in these peptides. For the binding data, the optimal regression equation explained 81% of the variance, and indicated the importance of the steric function at [Pro 2] and simple connectivity functions at [Gln6] and [Tyr8]. The optimal functional regression equation (80% of variance) confirmed the importance of connectivity functions at [Gln6] and [Tyr8], as well as the shape of residues [Lys1] and [Pro4]. The potencies of most full-length peptides were well predicted using the leave-one-out procedure, as were the potencies of a series of model Ala-substituted BUFs, thus emphasising the potential utility of these equations in the design of new ligands interacting with tachykinin receptors.

Original languageEnglish
Pages (from-to)329-338
Number of pages10
JournalBiochemical Pharmacology
Volume69
Issue number2
DOIs
Publication statusPublished - Jan 15 2005
Externally publishedYes

Keywords

  • Amphibian
  • Binding
  • Bufokinin
  • Functional
  • Intestine
  • Non-mammalian
  • QSAR
  • Structure-activity
  • Substance P
  • Tachykinin receptors
  • Tachykinins

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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