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Vol. 285, Issue 3, 995-1004, June 1998
Department of Pharmacology and Toxicology, Virginia Commonwealth
University, Medical College of Virginia Campus, Richmond, Virginia
(J.L.W., D.R.C., B.R.M.) and
Department of Chemistry, Clemson
University, Clemson, South Carolina (D.D., J.A.H.L., M.P., J.W.H.)
Early molecular modeling studies with
9-tetrahydrocannabinol (9-THC) reported
that three discrete regions which interact with brain cannabinoid (CB1)
receptors corresponded to the C-9 position of the cyclohexene ring, the
phenolic hydroxyl and the carbon side chain at the C3 position.
Although the location of these attachment points for aminoalkylindoles
is less clear, the naphthalene ring, the carbonyl group and the
morpholinoethyl group have been suggested as probable sites. In this
study, a series of indole- and pyrrole-derived cannabinoids was
developed, in which the morpholinoethyl group was replaced with another
cyclic structure or with a carbon chain that more directly corresponded
to the side chain of 9-THC and were tested for CB1
binding affinity and in a battery of in vivo tests,
including hypomobility, antinociception, hypothermia and catalepsy in
mice and discriminative stimulus effects in rats. Receptor affinity and
potency of these novel cannabinoids were related to the length of the
carbon chain. Short side chains resulted in inactive compounds, whereas
chains with 4 to 6 carbons produced optimal in vitro and
in vivo activity. Pyrrole-derived cannabinoids were
consistently less potent than were the corresponding indole derivatives
and showed pronounced separation of activity, in that potencies for
hypomobility and antinociception were severalfold higher than potencies
for hypothermia and ring immobility. These results suggest that,
whereas the site of the morpholinoethyl group in these cannabinoids
seems crucial for attachment to CB1 receptors, the exact structural
constraints on this part of the molecule are not as strict as
previously thought.
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