Synthesis and Pharmacological Characterization of N super(3)- Substituted Willardiine Derivatives: Role of the Substituent at he 5-Position of the Uracil Ring in the Development of Highly Potent and Selective GLU sub(K5) Kainate Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 50; no. 7; pp. 1558 - 1570
• Main Authors: Dolman, N P, More, JCA, Alt, A, Knauss, J L, Pentikaeinen, O T, Glasser, C R, Bleakman, D, Mayer, M L, Collingridge, G L, Jane, DE
• Format: Journal Article
• Language: English
• Published: 05.04.2007
• ISSN: 0022-2623
• DOI: 10.1021/jm061041u

Some N super(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 sub(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 sub(K5)-containing kainate receptors (K sub(B) values of 7 plus or minus 1 and 5 plus or minus 1 nM for antagonism of recombinant human GLU sub(K5) and GLU sub(K5)/GLU sub(K2), respectively) but displayed IC sub(50) values >100 mu M for antagonism of GLU sub(A2), GLU sub(K6), or GLU sub(K6)/GLU sub(K2).