SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF N-(2,5-DISUBSTITUTED PHENYL)-N'-(3-SUBSTITUTED PHENYL)-N'-METHYLGUANIDINES AS N-METHYL-D-ASPARTATE RECEPTOR ION-CHANNEL BLOCKERS

In the mammalian central nervous system, the N-methyl-D-aspartate (NMD A) subclass of glutamate receptors may play an important role in brain diseases such as stroke, brain or spinal cord trauma, epilepsy, and c ertain neurodegenerative diseases. Compounds which specifically antago nize the actions of the neurotransmitter glutamate at the NMDA recepto r ion-channel site offer a novel approach to treating these disorders. CERESTAT (4, aptiganel CNS 1102) is currently undergoing clinical tri al for the treatment of traumatic brain injury and stroke. Previously, we reported that analogues of N-1-naphthyl-N'-(3-ethylphenyl)-N'-meth ylguanidine (4) bound to the NMDA receptor ion-channel site with high potency and selectivity. Recently, molecules active at both a receptor s and NMDA receptor sites were investigated. A series of substituted d iphenylguanidines 6 which are structurally related to N-1-naphthyl-N'- (3-ethylphenyl)-N'-methylguanidine was prepared. Compounds containing appropriate substitution pattern in one of the phenyl rings of dipheny lguanidines displayed high affinity. For example, bromophenyl)-N'-(3-e thylphenyl)-N'-methylguanidine (27b, R-2 = R-5 = Br, R-3 = C2H5) exhib ited potency at both a receptors and NMDA receptor sites; 27b also sho wed high efficacy in vivo in a neonatal rat excitotoxicity model. Furt her studies indicated that substituent effects were important in this compound series, and 2,5-disubstituted phenyl was the preferred substi tution pattern for high-affinity binding at NMDA receptor sites. Bromo and methylthio were the optimal substituents for the R-2 and R-5 posi tions of the 2,5-disubstituted phenyl group, respectively. (2-Bromo-5- (methylthio)phenyl)-N'-(3-ethylphenyl)- N'-methylguanidine (34b, R-2 = Br, R-5 = SMe, R-3 = C2H5) was highly active at NMDA receptor sites. We found that the binding affinity of guanidines of type 6 could be fu rther enhanced with the appropriate substitution at R-3. Optimal activ ity in this series are afforded by 43b and 44b (R-2 = Cl or Br, R-5 = R-3 = SCH3). Both 43b and 44b bound to NMDA receptor sites with high p otency and selectivity (K-i vs [H-3]MK-801: 1.87 and 1.65 nM, respecti vely); these compounds are active in vivo in various animal models of neuroprotection. The structure-activity relationships for-these compou nds at the NMDA receptor ion-channel site are discussed.