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 synthesi zed 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 comm ercially available 1-naphthylethyl bromide 9 using the chain lengtheni ng sequences as shown in Scheme 3. In receptor binding assay and in vi vo testing, the long chain alkoxy compounds 3g and 3h (K-i = 127 nM) s howed 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 anal ogues 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 re tains activity. The present work points to the importance of the role of a keto group in the interaction with the receptor. Molecular modeli ng work suggests that, although reasonable superposition of key struct ural features between Delta(9)-THC and AAIs can be made, the overlay i s not straightforward. The present study also illustrates the difficul ty in accommodating AAIs into the cannabinoid pharmacophore and it see ms likely that a unique pharmacophore will need to be developed. Only then will the similarities to and differences from the classical canna binoid pharmacophore be clearly delineated. (C) 1997 Elsevier Science Ltd.