Synthesis and structure-activity relationship of C5-substituted analogues of (±)-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine [(±)-desmethyl-MK801]: Ligands for the NMDA receptor-coupled phencyclidine binding site

Article abstract of DOI:10.1021/jm00165a029

A series of eight C5-substituted analogues of (±)-10,11-dihydroy-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (±)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaboration of the C5-ethyl ester derivative. Analogues possessing large (e.g. propyl and larger) lipophilic substituents displace [³H]-1-(1-thienylcyclohexyl)piperidine ([³H]TCP) from the high-affinity phencyclidine (PCP) binding site in rat brain homogenates only at high concentrations (K(i) > 1000 nM); however, the presence of a polar amino functionality (e.g. 2-aminoethyl) offsets this effect (K(i) = 20 nM). Thus, the boundary condition for lipophilic substituents larger than ethyl appears to be polar in nature. Interaction of the 11 relatively small (MR <14) C5-substituted analogues of 1 with the high-affinity PCP binding site associated with the N-methyl-D-aspartate (NMDA) receptor is best described by the equation log (1/K(i)) = -5.83J + 0.64π + 7.41 (r = 0.90).