Reddy N L, Hu L Y, Cotter R E, Fischer J B, Wong W J, McBurney R N, Weber E, Holmes D L, Wong S T, Prasad R
Cambridge NeuroScience, Inc., Cambridge, Massachusetts 02139.
J Med Chem. 1994 Jan 21;37(2):260-7. doi: 10.1021/jm00028a009.
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.
二芳基胍作为N-甲基-D-天冬氨酸（NMDA）受体离子通道位点配体，代表了一类新型的潜在神经保护药物。合成了几种与已知的选择性σ受体配体N,N'-二邻甲苯基胍（DTG）结构相关的二芳基胍，并使用NMDA受体离子通道位点特异性放射性配体[3H]-(+)-5(S)-甲基-10(R),11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺（MK-801，3）以及σ受体特异性放射性配体[3H]-二邻甲苯基胍（DTG，5），在大鼠或豚鼠脑膜匀浆的体外放射性配体置换试验中对其进行了评估。本文介绍了新型三取代和四取代胍的构效关系，这些胍对NMDA受体离子通道位点具有高选择性，对σ受体的亲和力较弱或可忽略不计。对称取代的二苯基胍的体外结合结果表明，与对位取代衍生物相比，苯环上具有邻位或间位取代基（相对于胍氮的位置）的化合物对NMDA受体离子通道位点具有更高的亲和力。在研究的对称二芳基胍的环取代基组中，邻位优选异丙基，间位优选乙基。几种不对称胍，其中一个氮原子上含有萘环，第二个氮原子上含有邻位或间位取代的苯环，例如N-1-萘基-N'-(3-乙基苯基)胍（36），与相应的对称类似物相比，对NMDA受体离子通道位点的亲和力增加了3至5倍，而对σ受体的亲和力没有变化。在带有芳基环的胍氮原子上的额外小取代基产生了三取代和四取代胍衍生物，它们保留了对NMDA受体离子通道位点的亲和力，但对σ受体的亲和力显著降低。例如，N-1-萘基-N'-(3-乙基苯基)-N'-甲基胍（40）对NMDA受体离子通道位点具有高亲和力（IC50 = 36 nM，相对于[3H]-3），对σ受体具有低亲和力（IC；50 = 2540 nM，相对于[3H]-5）。对NMDA受体离子通道位点相对于σ受体的选择性似乎取决于带有芳基的胍氮原子上额外取代基的结构。在三取代和四取代二芳基胍中，甲基和乙基取代基是最优选的。三取代胍N-1-萘基-N'-(3-乙基苯基)-N'-甲基胍（40）及其紧密类似物在体内显示出良好的神经保护作用，是治疗中风和其他神经退行性疾病的潜在神经保护药物候选物。
