Characterization on the interaction of substance P with its receptor using substance P analogs containing Beta-methyl phenylalanine
Kahl, Brenda Friesenhahn
Substance P (SP) is an neuropeptide with the amino acid sequence Arg-Pro-Lys-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 and is believed to be involved in a variety of physiological responses. The purpose of this research was to study the key features necessary for substance P (SP) to interact with and activate its receptor. The two phenylalanines present at positions 7 and 8 have the most drastic effect on SP's ability to activate its receptor when substituted with nonaromatic amino acids. Conformationally constrained peptide analogs of phenylalanine, mainly P-pethylphenylalanine, were used to probe the steric elements necessary for receptor activation and to further understand how substance P interacts with its receptor. A methodical series of substituted substance P analogs were synthesized and a variety of techniques ranging from classical pharmacology to molecular biology were used to try to unlock the necessary features that are required by the phenylalanines at positions 7 and 8 to successfully activate the receptor and stimulate intracellular pathways. This study discovered that different cell types do not have the same structure activity relationship to these SP analogs. This leads to the conclusion that the G-proteins in these different cell types may influence the conformation of the receptor and cause the different structure activity relationships between cell types.