Design and synthesis of novel quinoxaline-2,3-dione AMPA/GlyN receptor antagonists: amino acid derivatives.
PNQX (1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3, 4-f]quinoxaline-2,3-dione) is a potent AMPA (IC50 = 0.063 microM) and GlyN (IC50 = 0.37 microM) receptor antagonist that was developed in our laboratories. While possessing a desirable in vitro and in vivo activity profile, this compound suffers from low aqueous solubility. In an effort to improve its potency and physical properties, we have designed and synthesized novel ring-opened analogues 4, 6, 9, and 11. Modeling analyses demonstrated that, while the 5-substituent in these analogues was forced to adopt an out-of-plane conformation due to steric contacts with neighboring substituents, the overall structure retained a good fit to a previously described AMPA pharmacophore model. This nonplanar orientation may lessen efficient packing in the solid state, compared to PNQX, leading to increased water solubility. Indeed, several nonplanar analogues containing appropriate functionalities, for example, the sarcosine analogue 9, were found to retain AMPA (IC50 = 0.14 microM) and GlyN (IC50 = 0.47 microM) receptor affinity and possess improved aqueous solubility compared to PNQX. The synthesis and the SAR of these compounds are discussed.
Nikam
S S
SS
Department of Chemistry, Parke-Davis Pharmaceutical Division/Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. sham.nikam@wl.com
Cordon
J J
JJ
Ortwine
D F
DF
Heimbach
T H
TH
Blackburn
A C
AC
Vartanian
M G
MG
Nelson
C B
CB
Schwarz
R D
RD
Boxer
P A
PA
Rafferty
M F
MF
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013574:Synaptosomes / Q000378:metabolism
C119804:((6-ethyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)methylamino)acetic acid; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D018009:Receptors, Glycine; D005998:Glycine