Selective NR1/2B N-methyl-D-aspartate receptor antagonists among indole-2-carboxamides and benzimidazole-2-carboxamides.
(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.
Borza
István
I
Gedeon Richter Ltd., Budapest 10, POB 27, H-1475, Hungary. i.borza@richter.hu
Bozó
Eva
E
Barta-Szalai
Gizella
G
Kiss
Csilla
C
Tárkányi
Gábor
G
Demeter
Adám
A
Gáti
Tamás
T
Háda
Viktor
V
Kolok
Sándor
S
Gere
Anikó
A
Fodor
László
L
Nagy
József
J
Galgóczy
Kornél
K
Magdó
Ildikó
I
Agai
Béla
B
Fetter
József
J
Bertha
Ferenc
F
Keserü
György M
GM
Horváth
Csilla
C
Farkas
Sándor
S
Greiner
István
I
Domány
György
G
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
C518980:(4-benzylpiperidin-1-yl)-(5(6)-hydroxy-1H-benzimidazol-2-yl)methanone; C518979:(4-benzylpiperidin-1-yl)-(6-hydroxy-1H-indol-2-yl)methanone; D000700:Analgesics; D001562:Benzimidazoles; D007211:Indoles; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium