Design and synthesis of thrombin receptor-derived nonpeptide mimetics utilizing a piperazine scaffold.
Focal thrombus formation and vasoconstriction serve to defend vessels when vascular damage occurs, but may be detrimental when an atherosclerotic plaque is disrupted. Recently, the identification of the platelet thrombin receptor opened a new area in the development of agents that may selectively inhibit the effects of thrombin on cells, without affecting fibrin formation. In this regard, we have synthesized a number of 1,4-disubstituted piperazines which are designed to be analogues of thrombin receptor activating peptides (TRAP) and carry the pharmacophoric features of Phe and Arg residues present in the active pentapeptide SFLLR. These compounds were tested in the rat aorta relaxation assay and in platelet aggregation studies and their biological activity was consistent with a direct action on thrombin receptor. Furthermore, the structure activity relationships confirmed the importance of Phe and Arg for receptor activation and the molecular modeling revealed an intriguing relationship between their amphipathic similarity with SFLLR and their biological activity.
Alexopoulos
K
K
Department of Chemistry, University of Patras, Greece.
Fatseas
P
P
Melissari
E
E
Vlahakos
D
D
Smith
J
J
Mavromoustakos
T
T
Saifeddine
M
M
Moore
G
G
Hollenberg
M
M
Matsoukas
J
J
D000818:Animals; D001011:Aorta; D001120:Arginine / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000737:chemistry / Q000494:pharmacology; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D018179:Receptors, Thrombin / Q000819:agonists*; D013329:Structure-Activity Relationship; D013698:Templates, Genetic; D013917:Thrombin / Q000737:chemistry*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
C090291:C186 65; D009842:Oligopeptides; D010879:Piperazines; D018179:Receptors, Thrombin; D014665:Vasodilator Agents; D000077489:Piperazine; D010649:Phenylalanine; D001120:Arginine; D013917:Thrombin