Quantitative structure-activity analyses of bufokinin and other tachykinins at bufokinin (bNK1) receptors of the small intestine of the cane toad, Bufo marinus.
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 [Pro2] 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.
Liu
Lu
L
Department of Physiology and Pharmacology, University of New South Wales, Sydney, NSW 2052, Australia.
Murray
Michael
M
Conlon
J Michael
JM
Burcher
Elizabeth
E
D019943:Amino Acid Substitution; D000818:Animals; D002024:Bufo marinus; D004305:Dose-Response Relationship, Drug; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D021281:Quantitative Structure-Activity Relationship; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015320:Tachykinins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D036341:Intercellular Signaling Peptides and Proteins; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C112071:bufokinin