Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.
Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).
Eissenstat
M A
MA
Department of Medicinal Chemistry, Sanofi Research Division, Sanofi Winthrop Inc., Collegeville, Pennsylvania 19426-0900, USA.
Bell
M R
MR
D'Ambra
T E
TE
Alexander
E J
EJ
Daum
S J
SJ
Ackerman
J H
JH
Gruett
M D
MD
Kumar
V
V
Estep
K G
KG
Olefirowicz
E M
EM
D000818:Animals; D048588:Benzoxazines; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D009025:Morpholines / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
D048588:Benzoxazines; D007211:Indoles; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone