220 G.A. Thakur et al.
Fig. 9.C-3 modified cannabinergic aminoalkylindoles
and CB 2 receptors and that aromatic stacking of the ligands with aromatic residues
in helices 3, 4, and 5 of both receptors may be an important interaction for AAIs at
these receptors (Burley and Petsko 1985; Huffman et al. 2003a; Reggio et al. 1998).
The spatial and electronic requirements of the C-3 substituent were further
explored by introducing a C-3 amide group (Bristol Myers Squibb). The AAI C-3
amide ligand 37 (Fig. 9) with a methoxy group at C-7, exhibited high CB 2 affinity
(Ki= 8 nM) and selectivity (CB 1 /CB 2 = 500) (Hynes et al. 2002). Replacement of the
amino acid moiety in 37 with theS-fenchylamine component resulted in slightly
reduced affinity for the CB 2 receptor (Ki= 30 nM). However, in theS-fenchyl amide
series, when the 2-methyl group in indole was replaced by hydrogen, the resulting
ligand ( 38 ,Fig.9)showedimprovedCB 2 affinity (Ki= 11 nM).
The 4-alkyloxy indole analogs were derived by translocating the C-3 substituent
of AAIs to C-4 via an ether linkage. Some of these exhibited in vivo cannabimimetic
activity, but most of them lacked cannabinoid receptor affinity (Dutta et al. 1997).