Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity.
In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.
Sax
Michael
M
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Germany.
Wünsch
Bernhard
B
D000818:Animals; D004148:Dioxolanes / Q000737:chemistry* / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004148:Dioxolanes; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C005840:dioxadrol; C579650:dexoxadrol; D010100:Oxygen; C084821:etoxadrol