The design of dipeptide helical mimetics: the synthesis, tachykinin receptor affinity and conformational analysis of 1,1,6-trisubstituted indanes.
The design and synthesis of conformationally constrained, nonpeptide templates (1,1,6-trisubstituted indanes) which allow the incorporation of two adjacent amino acid side chains, plus a third binding group in an orientation similar to that found in alpha-helices are reported. Six racemic and two homochiral Phe-Phe and Trp-Phe mimetics were synthesised and evaluated in tachykinin receptor binding assays as molecular probes for the binding conformation of the endogenous peptides. Several were found to bind with micromolar affinity to the NK1 and/or NK3 receptor. The conformation of one of the homochiral indanes, (1R)-N-((S)-1-hydroxymethylbenzyl)-1,6-dibenzylindan-1-carbo xamide, was analysed by X-ray crystallography and was found to be in an alpha-helix conformation.
Horwell
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DC
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, U.K.
Howson
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W
Ratcliffe
G S
GS
Willems
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HM
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D015288:Neurokinin A / Q000737:chemistry / Q000378:metabolism; D015287:Neurokinin B / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D018039:Receptors, Tachykinin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000737:chemistry / Q000378:metabolism
D004151:Dipeptides; D007189:Indans; D018039:Receptors, Tachykinin; D013373:Substance P; D015288:Neurokinin A; D015287:Neurokinin B