title: Nematocidal activity of MK-801 analogs and related drugs. Structure-activity relationships.
abstract: A series of dibenzo[a,d]cycloalkenimines were evaluated for their affinity to the (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) binding site in Caenorhabditis elegans membranes and their nematocidal activity. The (+)-MK-801 enantiomer (1) had a higher affinity (Kd = 240 nM) for its specific binding site and was a more potent nematocidal agent than the (-)-MK-801 enantiomer (-1). Ring expansion to form the dibenzo[a,d]cyclooctenimine analogs generally resulted in more potent compounds. The most potent of this series (23) was approximately 7-fold more potent than (+)-MK-801. A good correlation was established between binding affinities and nematocidal activity for all of the analogs that were tested. However, there was no correlation between binding to C. elegans membranes and affinity for mammalian MK-801 binding sites. Other noncompetitive inhibitors of the mammalian N-methyl-D-aspartate site were examined, and a series of diphenylguanidines were identified as potent competitive inhibitors of MK-801 binding to C. elegans membranes, in addition to displaying potent nematocidal activity. The most potent diphenylguanidine analog (24) was approximately 80-fold more potent than (+)-MK-801 in both its affinity for the MK-801 binding site and as a nematocidal agent. Molecular modeling studies support the hypothesis that the diphenylguanidines and MK-801 are binding to the same site and suggest that more potent compounds may be developed by effective modeling of the existing compounds.
authors.affiliation: Department of Cell Biochemistry and Physiology, Merck Research Laboratories, Rahway, NJ 07065-0900.
authors.forename: J M
authors.initials: JM
authors.lastname: Schaeffer
authors.forename: A R
authors.initials: AR
authors.lastname: Bergstrom
authors.forename: E G
authors.initials: EG
authors.lastname: Frazier
authors.forename: D
authors.initials: D
authors.lastname: Underwood
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D000969:Antinematodal Agents; D006146:Guanidines; D016291:Dizocilpine Maleate; C027773:diphenylguanidine