10,5-(Iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and derivatives. Potent PCP receptor ligands.
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.
Gee
K R
KR
Department of Chemistry, University of Oregon, Eugene 97403.
Barmettler
P
P
Rhodes
M R
MR
McBurney
R N
RN
Reddy
N L
NL
Hu
L Y
LY
Cotter
R E
RE
Hamilton
P N
PN
Weber
E
E
Keana
J F
JF
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D006168:Guinea Pigs; D051381:Rats; D017207:Rats, Sprague-Dawley; D017478:Receptors, Phencyclidine / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003986:Dibenzocycloheptenes; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D017478:Receptors, Phencyclidine; C082301:3-fluoro-10,5-(iminomethano)-10,11-dihydro-5H-dibenzo(a,d)cycloheptene; D018698:Glutamic Acid; D016291:Dizocilpine Maleate