SYNTHESIS AND STRUCTURE-ACTIVITY STUDIES OF N,N'-DIARYLGUANIDINE DERIVATIVES - (1-NAPHTHYL)-N'-(3-ETHYLPHENYL)-N'-METHYLGUANIDINE - A NEW, SELECTIVE NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST

Diarylguanidines, acting as NMDA receptor ion channel site ligands, re present a new class of potential neuroprotective drugs. Several diaryl guanidines structurally related to -N,N'-di-o- tolylguanidine (DTG), a known selective sigma receptor ligand, were synthesized and evaluated in in vitro radioligand displacement assays, with rat or guinea pig b rain membrane homogenates, using the NMDA receptor ion channel site sp ecific radioligand ),11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801, 3), and the sigma receptor-specific radioligand [H-3], di-o-t olylguanidine (DTG, 5). This paper presents the structure-activity rel ationships leading to novel tri- and tetrasubstituted guanidines, whic h exhibit high selectivity for NMDA receptor ion channel sites and wea k or negligible affinity for sigma receptors. The in vitro binding res ults from symmetrically substituted diphenylguanidines indicated that compounds having ortho or meta substituents (with respect to the posit ion of the guanidine nitrogen) on the phenyl rings showed greater affi nity for the NMDA receptor ion channel site compared with para-substit uted derivatives; Among the group of ring substituents studied for sym metrical diarylguanidines, an isopropyl group was preferred at the ort ho position and an ethyl group was preferred at the meta position. Sev eral unsymmetrical guanidines containing a naphthalene ring on one nit rogen atom and an ortho- or a meta-substituted phenyl ring on the seco nd nitrogen atom, e.g., N-1-naphthyl-N'-(3-ethylphenyl)guanidine (36), showed a 3-5-fold increase in affinity for the NMDA receptor ion chan nel site and no change in sigma receptor affinity compared to the resp ective symmetrical counterparts. Additional small substituents on the guanidine nitrogen atoms bearing the aryl I rings resulted in tri- and tetrasubstituted guanidine derivatives which retained affinity for NM DA receptor ion channel sites but exhibited a significant reduction in their affinities for a receptors. For example, N-1-naphthyl-N'-(3-eth ylphenyl)-N'-methylguanidine (40) showed high affinity for the NMDA re ceptor ion channel site (IC50 = 36 nM vs [H-3]-3) and low affinity for sigma receptors (IC50 = 2540 nM vs [H-3]-5). Selectivity for the NMDA receptor ion channel sites over sigma receptors appears to be depende nt upon the structure of the additional substituents on the guanidine nitrogen atoms bearing the aryl groups. Methyl and ethyl substituents are most preferred in the tri- and tetrasubstituted diarylguanidines. The trisubstituted guanidine, N-1-naphthyl-N'-(3-ethylphenyl)-N'-methy lguanidine (40) and its close analogues showed good in vivo neuroprote ction and are potential neuroprotective drug candidates for the treatm ent of stroke and other neurodegenerative disorders.