Synthesis and structure-activity relationships of selective ligands for P3 purinoceptor-like protein (P3LP).
We examined the structure-activity relationship of various 5'-N-substituted-carboxamidoadenosine derivatives toward P3 purinoceptor-like protein (P3LP), which has affinity for both adenine nucleosides and nucleotides. We discovered a hydrophobic binding region near the 5'-N-substituted-carboxamide group. From the linear alkyl N-substituted derivatives, 1-(adenin-9-yl)-1-deoxy-N-n-pentyl-beta-D-ribofuranuronamide (6) was found to be the most potent ligand. In the series of the N-cycloalkyl derivatives, 1-(adenin-9-yl)-1-deoxy-N-cyclohexyl-beta-D-ribofuranuronamide (8) was the strongest ligand. We also examined the receptor selectivity for the selected nucleosides 6 and 8 with 1 (HAK2701) and N-ethylcarboxamidoadenosine (NECA) versus P1 purinoceptor subtypes, such as adenosine A1, A2A, A2B, and A3 receptors and found 8 is the most selective ligand for P3LP.
Umino
T
T
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Yoshioka
K
K
Saitoh
Y
Y
Minakawa
N
N
Nakata
H
H
Matsuda
A
A
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D011983:Receptors, Purinergic / Q000145:classification / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D011983:Receptors, Purinergic; D018047:Receptors, Purinergic P1; D000241:Adenosine