DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF SPIDER TOXIN (ARGIOTOXIN-636) ANALOGS AS NMDA RECEPTOR ANTAGONISTS

Purpose. Twelve synthetic spider toxin analogs were prepared in an eff ort to better understand the structure-activity relationships of the p olyamine portion of argiotoxin-636 (Arg-636), a noncompetitive NMDA re ceptor (NMDAR) antagonist. Methods. The 1,13-diamino-4,8-diazatridecan e portion of the side chain of Arg-636 was systematically modified in an effort to further our knowledge of the structural requirements for the alkyl linker spacing between the amine nitrogens. Systematic isost eric replacement of each of the amine nitrogens in the polyamine moiet y with either oxygen or carbon provided a series of compounds which we re evaluated in vitro for NMDAR antagonist activity. Results. One-half of the heteroatoms found in Arg-636 were removed to provide analogs w hich maintained in vitro potency below 1 mu M. However, these simplifi ed analogs produced similar or more pronounced effects on the cardiova scular system than Arg-636 in vivo. Conclusions. In this set of analog s, a minimum of three basic nitrogens in the side chain was required f or maximum potency as NMDAR antagonists. Isosteric nitrogen substituti ons in the polyamine chain reduced the in vitro potency of these analo gs. An analog binding-conformation model was proposed to rationalize t he inactivity of these isosterically substituted analogs.