Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs).
Several novel 4-alkyloxy-aminoalkyl indole derivatives 3 were synthesized from 4-benzyloxyindole (1). Alkylation of 1 with 4-(2-chloroethyl)morpholine (NaH/HMPA) formed 2. Deprotection using palladium hydroxide on carbon/hydrogen followed by alkylation with the appropriate alkyl bromide gave the target compounds 3b-3j. In the synthesis of 3i and 3j, the appropriate alkyl bromides 13 and 17 were prepared from the commercially available 1-naphthylethyl bromide 9 using the chain lengthening sequences as shown in Scheme 3. In receptor binding assay and in vivo testing, the long chain alkoxy compounds 3g and 3h (Ki = 127 nM) showed affinity for the CB1 receptor which was approximately 16-35-fold less than that of WIN 55,225. However, the pharmacological profile of 3h mimics that of WIN 55,212. An examination of the SAR of these analogues shows that translocating the napthyl group in AAIs from the C-3 position to C-4 via an oxygen (ether linkage) decreases activity which is in contrast to previous findings that a naphthylcarbonyl at C-4 retains activity. The present work points to the importance of the role of a keto group in the interaction with the receptor. Molecular modeling work suggests that, although reasonable superposition of key structural features between delta 9-THC and AAIs can be made, the overlay is not straightforward. The present study also illustrates the difficulty in accommodating AAIs into the cannabinoid pharmacophore and it seems likely that a unique pharmacophore will need to be developed. Only then will the similarities to and differences from the classical cannabinoid pharmacophore be clearly delineated.
Dutta
A K
AK
Organix Inc., Woburn, MA 01801, USA.
Ryan
W
W
Thomas
B F
BF
Singer
M
M
Compton
D R
DR
Martin
B R
BR
Razdan
R K
RK
D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003511:Cyclohexanols / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D018716:Molecular Mimicry; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol