Structural Requirements for Cannabinoid Receptor Probes 221Fig. 10.Chemical structures of some aminoalkylindole-derived analogs
N-1 Aminoalkyl ChainA number of indole analogs bearing different aminoalkyl
substituents at N-1 weresynthesized (N-attached analogs, e.g., 34 ,Fig.9)andtested
(Eissenstat et al. 1995). This study found the aminoethyl substitution as an optimal
requirement with morpholino, thiomorpholino, and piperidino analogs showing
the highest activities. The respective acyclic amine and piperazine analogs were
inactive.
The Sterling Winthrop and Makriyannis laboratories further explored struc-
tural requirements at the N-1 position by synthesizing novel analogs in which the
aminoalkyl chain of the indole ring is attached to a heterocyclic amine through
a C–C bond. These analogs are generally more potent compared to the C–N analogs
and exhibit more favorable physicochemical properties. Potency was optimum for
N-methylpiperidinyl-2-methyl substitution at the N-1 position ( 39 , Fig. 10), while
activity resided predominately in theR-enantiomer (D’Ambra et al. 1996).
AM1241 ( 40 , Fig. 10), a highly CB 2 -selective and potent agonist (Ibrahim et
al. 2003; Malan et al. 2001) was recently developed by Makriyannis. Design of
this molecule incorporated theN-methylpiperidinyl-2-methyl substituent at the
N-1 position and a novel 2-iodo-5-nitrobenzoyl group at C-3. AM1241 exhibits
remarkably high peripheral analgesia in vivo and does not produce catalepsy,
hypothermia, inhibition of spontaneous locomotor activity, or impairment of per-
formance on the rotarod apparatus. The potential use of this CB 2 receptor agonist
for the treatment of neuropathic pain is being explored.