Key amino acids of vasopressin V1a receptor responsible for the species difference in the affinity of OPC-21268.
A non-peptide, vasopressin V1a receptor-selective antagonist, OPC-21268, exhibited a markedly higher affinity for the rat V1a receptor (Ki = 380 nM) than for the human V1a receptor (Ki = 140 microM). To delineate the region responsible for the high affinity binding of OPC-21268 for the rat V1a receptor, we have constructed a series of chimeric human and rat V1a receptors, and examined the chimeric and point-mutated receptors by competitive radioligand binding analysis. The results showed that the transmembrane domain (TMD) VI-VII of the vasopressin V1a receptor, in particular the amino acid residue Ala-342 in TMD VII, is the major component conferring the rat-selective binding of OPC-21268 to the V1a receptor.
Shinoura
H
H
Department of Molecular, Cell Pharmacology, National Children's Medical Research Center, Tokyo, Japan.
Take
H
H
Itoh
S
S
Hirasawa
A
A
Inoue
K
K
Ohno
Y
Y
Hashimoto
K
K
Tsujimoto
G
G
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D006801:Humans; D008969:Molecular Sequence Data; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D015363:Quinolones / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity
D000596:Amino Acids; D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; D011993:Recombinant Fusion Proteins; C068644:OPC 21268