Novel 3-aralkyl-7-(amino-substituted)-1,2,3-triazolo[4,5-d]pyrimidines with high affinity toward A1 adenosine receptors.
Three series of several 1,2,3-triazolo[4,5-d]pyrimidine derivatives bearing various amino substituents at the 7 position and one of three lipophilic substituents at the 3 position (benzyl, phenethyl, or 2-chlorobenzyl) were prepared starting from the corresponding 7-chloro compounds, by nucleophilic substitution by the appropriate amine. Radioligand binding assays at bovine brain adenosine A1 and A2A receptors showed that some compounds possessed a high affinity and selectivity for the A1 receptor subtype. In particular the biological results suggested the compounds bearing cycloalkylamino (cyclopentyl- and cyclohexylamino) or aralkylamino (alpha-methylbenzyl- and 1-methyl-2-phenylethylamino or amphetamino) substituents at the 7 position were the most active derivatives. The best lipophilic substituent at the 3 position was the 2-chlorobenzyl (A1 affinity Ki < 50 nM) followed by the benzyl and then the phenethyl groups. This pattern of structure-activity relationship (SAR) was similar to that previously reported for analogous 1,2,3-triazolopyridazino derivatives (Biagi et al., 1994, 1995, 1996) except for the compounds bearing substituted aromatic amines which presented a generalized and strong decrease of the A1 receptor affinity. These facts allowed us to attribute to these molecules a binding mode within the A1 adenosine receptor analogous to that of the corresponding triazolopyridazines.
Betti
L
L
Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Pisa, Italy.
Biagi
G
G
Giannaccini
G
G
Giorgi
I
I
Livi
O
O
Lucacchini
A
A
Manera
C
C
Scartoni
V
V
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D010627:Phenethylamines / Q000378:metabolism; D011724:Pyridazines / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D010627:Phenethylamines; D011724:Pyridazines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014230:Triazoles; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C047235:N-(1-methyl-2-phenylethyl)adenosine; D000241:Adenosine