The use of methyl substitution on the β-carbon of the phenylalanines of substance P (SP) analogs to probe the nature of the SP/receptor interaction

T. W. Reid, R. Saban, D. E. Bjorling, B. F. Kahl, D. M. Birney, R. D. Walkup, K. Ren, Christopher J Murphy

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Purpose. In order to make the smallest possible change in the SP molecule that would allow us to probe the nature of the SP receptor, we synthesized analogs that have a methyl group on the β-carbon of phenylalanine. Previous structure activity studies of SP have shown that the two phenylalanine (F) residues at positions 7 and 8 play a critical role in the ability of SP to bind and activate its receptor. Thus, we synthesized β-methyl F analogs of SP which will hinder the rotation of the phenyl ring around the bond between the α and β carbons. We examined whether the analogs could discriminate between different SP receptor subtypes. Methods. A β-methyl F residue was substituted for F in SP. Due to the existence of two enantiomers of β-methyl F and two F residues in SP, eight different SP analogs were synthesized. Structure activity studies were carried out by monitoring the ability of the different analogs to stimulate contraction of a rabbit iris smooth muscle and aorta. Results. It was found that mono-substitution of the two enantiomers of β-methyl F at either positions 7 or 8 resulted in four analogs of SP with either similar, better, or worse activity than SP. In contrast, the four di-substituted molecules did not follow a pattern consistent with the mono-substituted results. Also, the pattern for the rabbit aorta was not the same as the pattern for the rabbit iris. Conclusion. The small increase in steric bulk resulting from the substitution of a methyl group in the beta position of F can result in analogs of the SP molecule which can discriminate between the rabbit iris receptor and the rabbit aorta receptor. Thus, they represent different receptor subtypes.

Original languageEnglish (US)
JournalInvestigative Ophthalmology and Visual Science
Issue number3
StatePublished - Feb 15 1996
Externally publishedYes


ASJC Scopus subject areas

  • Ophthalmology

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