A comparative SAR study of thrombin receptor derived non peptide mimetics: importance of phenyl/guanidino proximity for activity.
Thrombin, the most potent physiological platelet agonist interacts with cells through a specific G protein-coupled receptor which has been cloned and sequenced. Synthetic thrombin receptor peptides (TRAPs) comprising the first 5 amino acids (SFLLR and SFLLR-NH2) of the new N-terminus tethered ligand of the thrombin receptor that is generated by thrombin's proteolytic activity were found to cause full platelet aggregation. During the screening of novel thrombin receptor derived non-peptide mimetics in the platelet aggregation assay we found that 1-phenylacetyl-4-(6-guanidohexanoyl)-piperazine (1) and 1-(6-guanidohexanoyl)-4-(phenylacetylamidomethyl)-piperidine (2) exerted in vitro antagonist activities (56% and 40% correspondingly) as it is depicted by the platelet aggregation assay. Using Molecular Modeling, the synthetic compounds were overlayed with SFFLR. All three superimposed low energy structures had Phe and Arg amino acids in spatial close proximity. The superimposition results revealed that 1 resembled more the stereoelectronic environment of SFLLR than 2. This difference may be related to their different antagonist efficacy.
Alexopoulos
K
K
Department of Chemistry, University of Patras, Greece.
Matsoukas
J
J
Tselios
T
T
Roumelioti
P
P
Mavromoustakos
T
T
Holada
K
K
D001120:Arginine; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010649:Phenylalanine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
C116669:1-(6-guanidohexanoyl)-4-(phenylacetylaminomethyl)piperidine; C116668:1-phenylacetyl-4-(6-guanidohexanoyl)piperazine; C090291:C186 65; D009842:Oligopeptides; D010455:Peptides; D010879:Piperazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; D010649:Phenylalanine; D001120:Arginine