Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration.
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Dziadulewicz
Edward K
EK
Novartis Institutes for BioMedical Research, 5 Gower Place, London, United Kingdom.
Bevan
Stuart J
SJ
Brain
Christopher T
CT
Coote
Paul R
PR
Culshaw
Andrew J
AJ
Davis
Andrew J
AJ
Edwards
Lee J
LJ
Fisher
Adrian J
AJ
Fox
Alyson J
AJ
Gentry
Clive
C
Groarke
Alex
A
Hart
Terance W
TW
Huber
Werner
W
James
Iain F
IF
Kesingland
Adam
A
La Vecchia
Luigi
L
Loong
Yvonne
Y
Lyothier
Isabelle
I
McNair
Kara
K
O'Farrell
Cathal
C
Peacock
Marcus
M
Portmann
Robert
R
Schopfer
Ulrich
U
Yaqoob
Mohammed
M
Zadrobilek
Jiri
J
D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
D000700:Analgesics; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C524107:naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone; D000242:Cyclic AMP