The definitive marijuana guide from Cannabis UK
Natural and Synthetic Endocannabinoids and Their Structure-Activity Relationships
by
Palmer SL, Khanolkar AD, Makriyannis A
ABSTRACT
During the past several years, cannabinoid biology
has witnessed marked advances that has propelled it to the forefront of
biomedical research. These new developments have also provided an opportunity
to examine the physiological and biochemical events underlying the use and
abuse of cannabis as well as elucidating the biological role of the endogenous
cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids
include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase
(AAH), and the carrier protein referred to as the anandamide transporter
(ANT). The identification of arachidonylethanolamide (anandamide, AEA) as
an endogenous cannabinoid has been an important development in cannabinoid
research which has led to the identification of two proteins associated
with cannabinoid physiology in addition to the CB1 and CB2 receptors. These
proteins are anandamide amidohydrolase (AAH), an enzyme responsible for
the hydrolytic breakdown of anandamide and the anandamide transporter (ANT),
a carrier protein involved in the transport of anandamide across the cell
membrane. Evidence obtained so far suggests that these two proteins, in
combination, are responsible for the termination of the biological actions
of anandamide. Also, the discovery of anandamide has revealed a novel class
of more selective agents possessing somewhat different pharmacological properties
than the cannabinoids. A number of such analogs have now been reported many
of which possess markedly improved cannabinoid receptor affinities and metabolic
stabilities compared to those of the parent ligand. Generally, anandamide
and all known analogs exhibit significant selectivities with high affinities
for the CB1 receptor and modest to very low affinity for the CB2 receptor.
In a relatively short period of time, pharmacological and biochemical studies
have confirmed initial speculations that anandamide is either a neuromodulator
or neurotransmitter and has significantly advanced our understanding of
cannabinoid biochemistry. This summary seeks to define the pharmacology
of endocannabinoids and to focus on the structure-activity relationships
(SAR) of anandamide for the CB1 cannabinoid receptor.
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