Minodronic acid, a third-generation bisphosphonate, antagonizes purinergic P2X(2/3) receptor function and exerts an analgesic effect in pain models.
The P2X(2/3) receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitor of bone resorption. We found that minodronic acid inhibited alpha,beta-methylene ATP-induced cation uptake with the potency higher than that of suramin in the P2X(2/3) receptor receptor-expressing cells. Other bisphosphonates did not show such activity. Subcutaneously administered (10-50 mg/kg) minodronic acid significantly inhibited the alpha,beta-methylene ATP-, acetic acid- and formalin-induced nociceptive behaviors in mice. These unique effects of minodronic acid would be beneficial for the treatment of accelerated bone turnover diseases accompanied by bone pain, including bone metastases.
Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Ibaraki, Japan. shuichirou.kakimoto@jp.astellas.com <shuichirou.kakimoto@jp.astellas.com>
Shuichiro
S
Kakimoto
Yukinori
Y
Nagakura
Seiji
S
Tamura
Tomonari
T
Watabiki
Kumiko
K
Shibasaki
Shohei
S
Tanaka
Masamichi
M
Mori
Masao
M
Sasamata
Masamichi
M
Okada
D019342:Acetic Acid; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D013997:Time Factors; D014162:Transfection
D018712:Analgesics, Non-Narcotic; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; C546402:P2rx2 protein, mouse; C546409:P2rx3 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; C087958:YM 529; D005557:Formaldehyde; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D019342:Acetic Acid