Involvement of adenosine A2a receptor in intraocular pressure decrease induced by 2-(1-octyn-1-yl)adenosine or 2-(6-cyano-1-hexyn-1-yl)adenosine.
The aim of the present study is to clarify the mechanism for the decrease in intraocular pressure by 2-alkynyladenosine derivatives in rabbits. The receptor binding analysis revealed that 2-(1-octyn-1-yl)adenosine (2-O-Ado) and 2-(6-cyano-1-hexyn-1-yl)adenosine (2-CN-Ado) selectively bound to the A(2a) receptor with a high affinity. Ocular hypotensive responses to 2-O-Ado and 2-CN-Ado were inhibited by the adenosine A(2a)-receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), but not by the adenosine A(1)-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or the adenosine A(2b)-receptor antagonist alloxazine. In addition, 2-O-Ado and 2-CN-Ado caused an increase in outflow facility, which was inhibited by CSC, but not by DPCPX or alloxazine. Moreover, 2-O-Ado and 2-CN-Ado increased cAMP in the aqueous humor, and the 2-O-Ado-induced an increase in cAMP was inhibited by CSC. These results suggest that 2-O-Ado and 2-CN-Ado reduced intraocular pressure via an increase in outflow facility. The ocular hypotension may be mainly mediated through the activation of adenosine A(2a) receptor, although a possible involvement of adenosine A(1) receptor cannot be completely ruled out. 2-O-Ado and 2-CN-Ado are useful lead compounds for the treatment of glaucoma.
Konno
Takashi
T
Drug Research Section II, Fukushima Research Laboratories, Toa Eiyo Ltd., Iizaka, Fukushima, Japan. konno.takashi@toaeiyo.co.jp
Murakami
Akira
A
Uchibori
Takehiro
T
Nagai
Akihiko
A
Kogi
Kentaro
K
Nakahata
Norimichi
N
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000480:Alkynes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology*; D007700:Kinetics; D008297:Male; D011817:Rabbits; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*
C504088:2-(6-cyano-1-hexyn-1-yl)adenosine; D000480:Alkynes; D043705:Receptor, Adenosine A2A; C070494:YT 146; D000242:Cyclic AMP; D000241:Adenosine