Synthesis of 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as novel, potent, and selective alpha1-adrenoceptor ligands.
Novel compounds characterized by a pyrrolo[3,2-d]pyrimidine-2,4-dione (PPm) system connected through an alkyl chain to a phenylpiperazine (PPz) residue were designed as structural analogues of the alpha(1)-adrenoceptor (alpha(1)-AR) ligand RN5 (1). In this new series of derivatives an arylpyrrolo moiety has replaced the indole nucleus of RN5. Several structural modifications were performed on the PPm and PPz moieties and the connecting alkyl chain. These compounds were synthesized and tested in radioligand binding experiments where many of them showed interesting binding profiles. Some compounds, including 31, 34, and 36, displayed substantial alpha(1)-AR selectivity with respect to serotoninergic 5-HT(1A) and dopaminergic D(1) and D(2) receptors. Two different molecular modeling approaches (pharmacophoric mapping and quantitative structure-affinity relationship analysis) have been applied to rationalize, at a quantitative level, the relationships between affinity toward alpha(1)-ARs and the structure of the studied compounds. Several QSAR models have been reported and described, accounting for the influence of various molecular portions on such affinity data.
Patanè
Emanuele
E
Dipartimento di Scienze Farmaceutiche, Università di Catania, viale A. Doria 6, 95125 Catania, Italy. vpittala@unict.it
Pittalà
Valeria
V
Guerrera
Francesco
F
Salerno
Loredana
L
Romeo
Giuseppe
G
Siracusa
Maria Angela
MA
Russo
Filippo
F
Manetti
Fabrizio
F
Botta
Maurizio
M
Mereghetti
Ilario
I
Cagnotto
Alfredo
A
Mennini
Tiziana
T
D000465:Algorithms; D000818:Animals; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D018340:Receptors, Adrenergic, alpha-1