Purpose. Twelve synthetic spider toxin analogs were prepared in an effort to better understand the structure-activity relationships of the polyamine portion of argiotoxin-636 (Arg-636), a noncompetitive NMDA receptor (NMDAR) antagonist.

Methods. The l,13-diamino-4,8-diazatridecane 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 isosteric replacement of each of the amine nitrogens in the polyamine moiety with either oxygen or carbon provided a series of compounds which were evaluated in vitro for NMDAR antagonist activity.

Results. One-half of the heteroatoms found in Arg-636 were removed to provide analogs which maintained in vitro potency below 1 μM. However, these simplified analogs produced similar or more pronounced effects on the cardiovascular system than Arg-636 in vivo.

Conclusions. In this set of analogs, a minimum of three basic nitrogens in the side chain was required for maximum potency as NMDAR antagonists. Isosteric nitrogen substitutions in the polyamine chain reduced the in vitro potency of these analogs. An analog binding-conformation model was proposed to rationalize the inactivity of these isosterically substituted analogs.