Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives.
A series of N-8-arylpiperazinylpropyl derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2-10) and amide derivatives of 1,3-dimethyl-6,7-dihydroimidazo[2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic acid (11-13) were synthesized. Compounds (2-10) evaluated in vitro were potent 5-HT(1A) receptor ligands. Preclinical studies indicated that 8-[3-(N4-phenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2) exerts anxiolytic-like activity in the four-plate test in mice; however its effect was weaker, than that produced by Diazepam. This compound and 8-[3-(N4-2'-metoxyphenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (3) behaved like antidepressants in the forced swimming test in mice; and their activity in that model was comparable with the effect of Imipramine. The obtained results suggested that the long-chain arylpiperazines (LCAPs) linked to tricyclic derivatives of the theophylline remain a worthy of future research for obtaining new derivatives with potential anxiolytic/antidepressant activity.
Zagórska
Agnieszka
A
Department of Medicinal Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
Jurczyk
Sławomir
S
Pawłowski
Maciej
M
Dybała
Małgorzata
M
Nowak
Gabriel
G
Tatarczyńska
Ewa
E
Nikiforuk
Agnieszka
A
Chojnacka-Wójcik
Ewa
E
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives*
D000928:Antidepressive Agents; D007093:Imidazoles; D010879:Piperazines; D011687:Purines; D017448:Receptors, Dopamine D2; D044282:Receptor, Serotonin, 5-HT1A; D013806:Theophylline