Use of β-Methylphenylalanine (βMeF) Residues To Probe the Nature of the Interaction of Substance P with Its Receptor: Effects of βMeF-Containing Substance P Analogs on Rabbit Iris Smooth Muscle Contraction

David M. Birney, Derek C. Cole, Craig E. Crosson, Brenda F. Kahl, Bart W. Neff, Ted W. Reid, Kaijun Ren, Robert D. Walkup

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Abstract

The effects of substituting (2S,3S)-β-methylphenylalanine (S-βMeF) or (2S,3R)-β-methylphenylalanine (R-βMeF) for the Phe7 and/or Phe8 residues of the tachykinin substance P (SP, RPKPQQFFGLM-NH2) upon the ability of SP to stimulate contraction of the rabbit iris smooth muscle were investigated. The eight βMeF-containing SP analogs (four monosubstituted analogs, four disubstituted analogs) 1-8 were synthesized and found to be agonists of SP in the smooth muscle contraction assay, having EC50 values ranging from 0.15 to 10.0 nM. Three analogs are significantly more active than SP [8R-(βMeF)SP (4), 7S,8S-(βMeF)2SP (5), and 7-R,8S-(/3MeF)2SP (6)], three analogs are approximately equipotent with SP [7S-(βMeF)SP (1), 7R-(βMeF)SP (2), and 7S,8R-(βMeF)2SP (8)], and two analogs are significantly less active than SP [8S-(βMeF)SP (3) and 7R,8R-(βMeF)2SP (7)]. The effects of the βMeF substitutions upon the activity of SP are not additive and cannot be explained using simple conformational models which focus only on the side chain conformations of the βMeF residues. It is postulated that the βMeF residues induce minor distortions in the peptide backbone with resultant consequences upon peptide-receptor binding which are not dictated solely by the side chain conformations. This idea is consistent with 1H-NMR data for the monosubstituted analogs 1-4, which imply that the βMeF substitutions cause slight distortions in the peptide backbone and that the βMeF side chains are assuming trans or gauche(-) conformations.

Original languageEnglish
Pages (from-to)2478-2482
Number of pages5
JournalJournal of Medicinal Chemistry
Volume38
Issue number13
DOIs
StatePublished - Jun 1 1995

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