Ramachander Gollamudi

Relationships between chemical structure and inhibition of epinephrine-induced human blood platelet aggregation

The effect of structural features in a series of carbamoylpiperidine and nipecotoylpiperazine congeners on epinephrine-induced aggregation of human blood platelets is examined. Epinephrine-induced primary aggregation is effectively inhibited by the nipecotoylpiperazine derivatives (culminating at an IPA50 of 11.9 microM). While among nipecotoylpiperazine as well as carbamoylpiperidine congeners there are potent inhibitors of ADP-stimulated platelet function (cresting at an IA50 of 12.4 and 11.4 microM, respectively), the carbamoylpiperidine analogs are much less active (e.g., IPA50 of 298.1), or practically inactive, in impeding epinephrine-induced primary aggregation (PA).

Some Novel Inhibitors of Platelt Aggregation: Acute Toxicity in Mice and Ita Relationship to in Vitro Activity and Toxicity

Five carbamoylpiperidine congeners and one nipecotoylpiperazine derivative, which inhibit ADP-induced aggregation of human blood platelets in vitro, were evaluated in vivo for acute toxicity to male and female ICR mice. Although the in vitro platelet aggregation inhibiting potency of these compounds covered about a 1150-fold range, the acute ip LD50s (microM/kg) in mice showed only a fourfold range of values. An increase in platelet aggregation inhibiting potency (in vitro) was not paralleled by an increase in acute toxicity in vivo for these compounds; in fact, the most potent aggregation inhibitor (microM/liter) was the least toxic (microM/kg) to mice. A comparison of acute LD50s (microM/kg) to concentrations which produce 50% inhibition of mouse fibroblast cell growth in culture (microM/liter) did not yield a consistent value, nor was the rank order of toxicity the same from these two tests. In hematoxylin and eosin stained slides of major organs from treated mice, no histopathologic lesions were observed which were attributable to administration of these compounds.

Effects of novel aggregation inhibitors on serotonin uptake by human blood platelets

Novel aggregation inhibitors blocked serotonin uptake by human blood platelets in concentrations ranging from 0.7 +/- 0.1 microM to 237.5 +/- 35.7 microM; a modified procedure, validated by kinetic analysis, was employed in which pH drift was minimized to 0.03 during the active assay period. Structural features in carbamoylpiperidine and nipecotoylpiperazine derivatives which actually constitute molecular probes, and show remarkable specificity for aggregation-inhibitory target sites, disclosed striking differences between the latter and serotonin receptors or other loci affecting serotonin uptake.