Synthesis and pharmacological characterization of N-3-substituted willardiine derivatives: Role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLU(K5) kainate receptor antagonists

: Dolman NP, More JCA, Alt A, Knauss JL, Pentikainen OT, Glasser CR, Bleakman D, Mayer ML, Collingridge GL, Jane DE

Publisher: AMER CHEMICAL SOC

: 2007

: Journal of Medicinal Chemistry

: JOURNAL OF MEDICINAL CHEMISTRY

: J MED CHEM

: 50

: 7

: 1558

: 1570

: 13

: 0022-2623

DOI: https://doi.org/10.1021/jm061041u

Some N-3-substituted analogues of willardiine such as 11 and 13 are selective kainate receptor antagonists. In an attempt to improve the potency and selectivity for kainate receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLU(K5) revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLU(K5)-containing kainate receptors (K-B values of 7 +/- 1 and 5 +/- 1 nM for antagonism of recombinant human GLU(K5) and GLU(K5)/GLU(K2), respectively) but displayed IC50 values > 100 mu M for antagonism of GLU(A2), GLU(K6), or GLU(K6)/GLU(K2).