Inhibition of platelet adhesion and thrombus formation on a collagen-coated surface by novel carbamoylpiperidine antiplatelet agents

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Abstract

The inhibitory effect of two novel antiplatelet agents, 1,10-bis-(N,N-diethylcarbamoyl)piperidono]decane dihydrobromide (G-110) and 1,6bis[3-(N,N-diethylcarbamoyl)piperidino]hexane dihydrobromide (G-112) on platelet adhesion and subsequent aggregation on collagen-coated surface was evaluated under controlled flow. Glass coverslips coated with bovine fibrillar collagen type I were exposed to heparinized human whole blood that had been preincubated with either aqueous solutions of one of the two carbamoylpiperidine congeners or corresponding amounts (1.0–4.0 μl/ml blood) of distilled water, at a wall shear rate of 1000 s−1, in a parallel-plate perfusion chamber. Epifluorescence video microscopy with a microphotometric measurement technique was used to visualize and quantify deposition of fluorescently-labeled platelets from flowing whole blood onto the collagen-coated surface. At concentrations of 100 and 200 μM, G-110 inhibited platelet accumulation by 30±9% (±S.E.) and 63±3% (±SE), respectively; while G-112 reduced platelet deposition by 19±3% (±SE) and 31±2% (±SE) at concentrations of 200 and 400 μM, respectively. Digital image processing techniques were used to analyze the dynamics of thrombus growth on the collagen-coated surfaces. It was found that the compounds reduced the rate of thrombus growth by impeding both surface coverage and the number of platelets per thrombus in a concentration-dependent manner. This study, together with others on related compounds GT-12, BPAT-117 and BPAT-143, corroborates the nature of pivotal features in the molecular structure of carbamoylpiperidine and nipecotoylpiperazine derivatives which enhance desirable antithrombotic effects, e.g. intramolecular distance between two tertiary amines (ring nitrogens) and levels of hydrophobicity.

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