Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine.
Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizures (MES) in rats when given po. The differences in anti-MES activity for these analogues was not explained by differences in pKa or lipophilicity. However, the four classes of heterocycles have distinctly different calculated electrostatic isopotential maps, which may be related to optimum anticonvulsant activity.
Kelley
J L
JL
Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709, USA.
Davis
R G
RG
McLean
E W
EW
Glen
R C
RC
Soroko
F E
FE
Cooper
B R
BR
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D011687:Purines; D011743:Pyrimidines; C050493:9-(2-fluorobenzyl)-6-(methylamino)-9H-purine