POLYAMINE SULFONAMIDES WITH NMDA ANTAGONIST PROPERTIES ARE POTENT CALMODULIN ANTAGONISTS AND CYTOTOXIC AGENTS

N-1-Dansylspermine and related sulfonamides of the natural polyamines are very potent blockers of NMDA-type glutamate receptors. They exhibi t pharmacological properties which were not predicted from the constit uents of the conjugates. Cytotoxicity and calmodulin antagonism of N-1 -dansylspermine were especially impressive. Calmodulin antagonism impl ies that N-1-dansylspermine prevents induction of ornithine decarboxyl ase and inhibits its own active uptake via the polyamine transport sys tem. Structure-activity considerations demonstrated that an aromatic c haracter of the substituent is not required; amide bond formation with an aliphatic sulfonic acid is sufficient to transform spermine into a highly toxic calmodulin antagonist. Cytotoxicity and calmodulin antag onism are properties which are intrinsic to spermine, but they are obs erved only at very high concentrations. Amide bond formation at N-1 wi th a lipophilic residue appears to 'amplify' these normally latent pro perties. The use of polyamine conjugates structurally related to the a mides described in this work for targeting tumours may be marred by th eir calmodulin antagonism. (C) 1998 Elsevier Science Ltd. All rights r eserved.