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

Abstract

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.

Experimental and computational study on the energetics of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene (dibenzosuberane)

“…The computational estimates obtained using equations (5) to (8) are in good agreement with the experimental value with a maximum deviation of 9.0 kJ Á mol À1 . Using equation (9) the computational estimates are very different from the experimental value.…”

“…These compounds have been reported as being antidepressants [2], the most well known being amitriptyline (3-(10,11-dihydro-5H-dibenzo[[a,d]]cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine) [3]. Dizocilpine (5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine), also known as MK-801, displays potent anticonvulsant and neuroprotective properties [4][5][6][7].…”

Chlorinated phenyl azides as photolabeling reagents. Synthesis of an ortho,ortho'-dichlorinated arylazido PCP receptor ligand

“…Synthesis of 3-Azido-2,4-dichloro-IDDC (19). The photoaffinity labeling and characterization of the PCP site in mammalian brain has been an ongoing project in our laboratory (26)(27)(28)(29). A problem encountered which is common to receptor photoaffinity labeling approaches has been a low efficiency of nitrene insertion of the activated photoaffinity label into the receptor protein (27).…”

“…Thus far photolabeling approaches have utilized aromatic azides such as 3-azido-MK801 (13) (27,28) that do not have halogen atoms ortho to the azido group. It was therefore of interest to synthesize dichloroazide 19, a derivative of the potent PCP receptor ligand 10,5-(iminomethano)-10,1 l-dihydro-5H-dibenzo [o,d] cycloheptene (26) (IDDC, 14) (Scheme I) as a potentially efficient photolabel.…”

Asymmetric Electrochemical Arylation in the Formal Synthesis of (+)-Amurensinine

“…1 Isopavine alkaloids [2][3][4][5] represent a diverse family of alkaloids that commonly have been isolated from a widespread series of natural sources, exhibiting remarkable biological properties (Figure 1a). 6 From a synthetic standpoint, the enantioselective enolate arylation would provide a simple and straightforward approach to generate key structural motifs I with α,α-diaryl tertiary chiral carbon centers in a stereoselective manner. [7][8][9][10] However, the racemization via enolization process is associated with the stereoselective preparation of α,α-diaryl carbonyl architecture (Figure 1b).…”