ABSTRACT
The drugs tolazoline, clonidine, lofexidine, and fenmetozole were found to inhibit the gelation of hemoglobin S in the order of increasing effectiveness. Only the latter, however, reduced the sickling of red cells significantly and normalized the oxygen affinity of SS blood at 5-10 mM concentrations. Since this level of drug is lower than those reported for many other anti-sickling agents to achieve comparable effects, the 2-imidazoline class of compounds may provide important clues for the development of therapy for sickle cell anemia.
Subject(s)
Anemia, Sickle Cell/blood , Antisickling Agents , Clonidine/analogs & derivatives , Clonidine/pharmacology , Hemoglobin, Sickle/metabolism , Imidazoles/pharmacology , Tolazoline/pharmacology , Gels , Humans , Kinetics , Oxyhemoglobins/metabolism , Structure-Activity RelationshipABSTRACT
Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.
