Document Detail


Structure-activity studies at the rat tachykinin NK2 receptor: effect of substitution at position 5 of neurokinin A.
MedLine Citation:
PMID:  10231723     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
A Comis; E Burcher
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
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:
Created Date:  1999-07-14     Completed Date:  1999-07-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9707067     Medline TA:  J Pept Res     Country:  DENMARK    
Other Details:
Languages:  eng     Pagination:  337-42     Citation Subset:  IM    
Affiliation:
School of Physiology and Pharmacology, University of New South Wales, Australia.
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MeSH Terms
Descriptor/Qualifier:
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:
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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