| Structure-activity studies at the rat tachykinin NK2 receptor: effect of substitution at position 5 of neurokinin A. | |
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MedLine Citation:
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PMID: 10231723 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A series of analogues of neurokinin A(4-10) was synthesized using solid phase techniques with Chiron pins, and purified by HPLC. The potencies of 10 peptides with substitution at Ser5 were assessed at rat fundus NK2 receptors. In membrane binding studies with [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10), all compounds except [Asp5]NKA(4-10) showed reasonable affinity, and analogues with Lys and Arg substitutions were five-fold more potent than NKA(4-10). In functional studies, all peptides were able to contract the rat isolated fundus strips. Analogues with Phe, His and Asn substitutions were substantially weaker in functional than in binding studies, whereas there was an excellent correlation (r = 0.95) between binding and functional potency for the remaining seven peptides. [Phe5]NKA(4-10) is in fact neurokinin B(4-10) and this residue may be critical in determining selectivity between NK2 and NK3 receptors. Analogues with a basic residue (Lys, Arg) at position 5 showed both increased affinity and functional potency, whereas the neutral [Asn5]NKA(4-10) was equally as weak in contractile studies as the acidic [Asp5]NKA(4-10). However, [Glu5]NKA(4-10) and [Gln5]NKA(4-10) were no different from NKA(4-10). Our results could indicate the presence of a negative charge on the NK2 receptor, close to position 5 of NKA. This would facilitate interaction with positively charged side chains and impede interaction with negatively charged side chains, particularly the inflexible side chain of aspartic acid. Thus, not only the charge, but also the length of the side chain of the residue at position 5, seems to be important for interaction with the rat NK2 receptor. |
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Authors:
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A Comis; E Burcher |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The journal of peptide research : official journal of the American Peptide Society Volume: 53 ISSN: 1397-002X ISO Abbreviation: J. Pept. Res. Publication Date: 1999 Mar |
Date Detail:
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Created Date: 1999-07-14 Completed Date: 1999-07-14 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9707067 Medline TA: J Pept Res Country: DENMARK |
Other Details:
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Languages: eng Pagination: 337-42 Citation Subset: IM |
Affiliation:
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School of Physiology and Pharmacology, University of New South Wales, Australia. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chromatography, High Pressure Liquid Kinetics Male Neurokinin A / chemistry Peptide Biosynthesis Protein Binding Rats Rats, Wistar Receptors, Neurokinin-2 / chemistry* Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Neurokinin-2; 86933-74-6/Neurokinin A |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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