Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist.
Diarylguanidines, acting as NMDA receptor ion channel site ligands, represent a new class of potential neuroprotective drugs. Several diarylguanidines 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 brain membrane homogenates, using the NMDA receptor ion channel site specific radioligand [3H]-(+)-5(S)-methyl-10(R),11-dihydro-5H-dibenzo[a,d]cyclohepten-5 ,10- imine (MK-801, 3), and the sigma receptor-specific radioligand [3H]-di-o-tolylguanidine (DTG, 5). This paper presents the structure-activity relationships leading to novel tri- and tetrasubstituted guanidines, which exhibit high selectivity for NMDA receptor ion channel sites and weak or negligible affinity for sigma receptors. The in vitro binding results from symmetrically substituted diphenylguanidines indicated that compounds having ortho or meta substituents (with respect to the position of the guanidine nitrogen) on the phenyl rings showed greater affinity for the NMDA receptor ion channel site compared with para-substituted derivatives. Among the group of ring substituents studied for symmetrical diarylguanidines, an isopropyl group was preferred at the ortho position and an ethyl group was preferred at the meta position. Several unsymmetrical guanidines containing a naphthalene ring on one nitrogen atom and an ortho- or a meta-substituted phenyl ring on the second 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 channel site and no change in sigma receptor affinity compared to the respective symmetrical counterparts. Additional small substituents on the guanidine nitrogen atoms bearing the aryl rings resulted in tri- and tetrasubstituted guanidine derivatives which retained affinity for NMDA receptor ion channel sites but exhibited a significant reduction in their affinities for sigma receptors. For example, N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (40) showed high affinity for the NMDA receptor ion channel site (IC50 = 36 nM vs [3H]-3) and low affinity for sigma receptors (IC50 = 2540 nM vs [3H]-5). Selectivity for the NMDA receptor ion channel sites over sigma receptors appears to be dependent 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'-methylguanidine (40) and its close analogues showed good in vivo neuroprotection and are potential neuroprotective drug candidates for the treatment of stroke and other neurodegenerative disorders.
Reddy
N L
NL
Cambridge NeuroScience, Inc., Cambridge, Massachusetts 02139.
Hu
L Y
LY
Cotter
R E
RE
Fischer
J B
JB
Wong
W J
WJ
McBurney
R N
RN
Weber
E
E
Holmes
D L
DL
Wong
S T
ST
Prasad
R
R
D000818:Animals; D001921:Brain / Q000187:drug effects; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D006146:Guanidines; D016194:Receptors, N-Methyl-D-Aspartate; C079779:aptiganel