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

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Abstract
A series of eight C5-substituted analogues of (.+-.)-10,11-dihydro-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-ethylester derivative. Analogues processing large (e.g.propyl and larter) 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 concentratiosn (Ki > 1000 nM); however, the presence of a polar amino functionality (e.g. 2-aminoethyl) offsets this effect (Ki = 20 nM). Thus, the boundary conditions 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/Ki) = 5.837 + 5.837 + 0.64.pi. + 7.41 (r = 0.90).