10,5-(Iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and derivatives. Potent PCP receptor ligands

• Published in: Journal of medicinal chemistry Vol. 36; no. 14; pp. 1938 - 1946
• Main Authors: Gee, Kyle R, Barmettler, Peter, Rhodes, Michael R, McBurney, Robert N, Reddy, N. Laxma, Hu, Lain Yen, Cotter, Ronald E, Hamilton, Philip N, Weber, Eckard, Keana, John F. W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 09.07.1993
• Subjects: Animals; Binding Sites; Brain - drug effects; Brain - metabolism; Cells, Cultured; Chemistry; Dibenzocycloheptenes - chemical synthesis; Dibenzocycloheptenes - chemistry; Dibenzocycloheptenes - pharmacology; Dizocilpine Maleate - metabolism; Exact sciences and technology; Excitatory Amino Acid Antagonists; Glutamates - toxicity; Glutamic Acid; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Organic chemistry; Preparations and properties; Rats; Rats, Sprague-Dawley; Receptors, Phencyclidine - drug effects; Receptors, Phencyclidine - metabolism; Stereoisomerism; Structure-Activity Relationship; Cyclization; Structure activity relation; Nitrogen heterocycle; Affinity; Aromatic compound; Tetracyclic compound; In vitro; Biological activity; Alkylation; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00066a002

IDDC (3, 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene++ +) and a series of substituted derivatives were synthesized and evaluated in vitro for their ability to displace tritiated MK-801 ([3H]-2) from its specific binding site in guinea pig brain homogenate. Substitution at the 3-position of 3 with bromine, chlorine, and fluorine led to increased binding affinity. In contrast, substitution of donor groups at the 3-position gave decreased binding affinities, as did all substitutions at the 7-position and on nitrogen. Where racemic mixtures were resolved, the (+)-optical antipodes were more active than their enantiomers or racemates. The most active ligand found in this study was (+)-13e (IC50 = 15.5 +/- 4.5 nM). The affinity of (+)-13e for the PCP receptor makes it among the most potent ligands known. In vitro neuroprotection was demonstrated by 3, (+)-3, and (+)-6 (N-Me-IDDC) against glutamate-induced cell death in rat hippocampal cells.