Covalent complexes of albumin with serotonin, ketanserin and lysergic acid antagonize the activity of serotonin in human platelets.
Covalent conjugates of bovine serum albumin (BSA) and 5-HT, ketanserin or d-lysergic acid were synthesized and characterized by polyacrylamide gel electrophoresis, whole blood clearance experiments in mice and aggregation studies with human platelets. Using the standard synthesis procedure, each mol of BSA bound 13.4 mol of [3H]5-HT. Derivatization did not cause significant protein aggregation as determined by electrophoresis. All three conjugates antagonized the ability of 5-HT to amplify aggregation caused by low concentrations of ADP. The antagonist activity of each conjugate was concentration dependent; 2.6 microM 5-HT-BSA completely inhibited the aggregation caused by 13 microM 5-HT. None of the BSA drug conjugates, including 5-HT-BSA, amplified platelet aggregation caused by ADP in the absence of 5-HT. Aggregation by ristocetin, collagen, epinephrine or ADP alone was not significantly affected by the conjugates. Whole blood elimination experiments in mice demonstrated that the three conjugates and underivatized BSA are equally stable in the circulation. These prototypic 5-HT drug-protein conjugates may be useful for probing 5-HT2 receptor-ligand interactions in human platelets.
VandenBerg
S R
SR
Department of Pathology, University of Virginia Health Sciences Center, Charlottesville 22908.
Gonias
S L
SL
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D004337:Drug Carriers; D004591:Electrophoresis, Polyacrylamide Gel; D004873:Ergolines / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology*; D008237:Lysergic Acid / Q000494:pharmacology*; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D013997:Time Factors
D004337:Drug Carriers; D004873:Ergolines; D010975:Platelet Aggregation Inhibitors; D012702:Serotonin Antagonists; D012710:Serum Albumin, Bovine; D012701:Serotonin; D000244:Adenosine Diphosphate; D007650:Ketanserin; D008237:Lysergic Acid