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The Endogenous Cannabinoids and the Control of Drug Craving. Alexandros Makriyannis, Director. D 9 - THC / D 8 -THC. (-)D 9 -tetrahydrocannabinol. (-)D 8 -tetrahydrocannabinol. Medicinal Uses for Cannabinoids. Analgesic Anticonvulsive Sedative Antidepressive Hypnotic Antiasthmatic. - PowerPoint PPT Presentation
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The Endogenous Cannabinoids and the Control of Drug Craving
Alexandros Makriyannis, Director
99-THC / / 88-THC-THC
O
OH
O
OH
99-tetrahydrocannabinol-tetrahydrocannabinol 88-tetrahydrocannabinol-tetrahydrocannabinol
Medicinal Uses for Cannabinoids
AnalgesicAnalgesic
AnticonvulsiveAnticonvulsive
SedativeSedative
AntidepressiveAntidepressive
HypnoticHypnotic
AntiasthmaticAntiasthmatic
ImmunomodulationImmunomodulation
Memory EnhancingMemory Enhancing
AnestheticAnesthetic
Birth ControlBirth Control
Appetite StimulationAppetite Stimulation
AntipyreticAntipyretic
Neuropathic PainNeuropathic Pain
AntiemeticAntiemetic
AntirheumaticAntirheumatic
AntimigraineAntimigraine
AntineuralgicAntineuralgic
Reduction of FatigueReduction of Fatigue
Two Cannabinoid Receptors: CB1 & CB2
264
257
CB1
e1e2
e3
i1i2
i3
174
179
CB2
e1e2
e3
i1i2
i3
ExtracellularExtracellular
472 amino acids472 amino acids 360 amino acids360 amino acids
Endogenous Cannabinoid Receptor Ligands
O
OOH
OHNH
O
OH
Anandamide 2-Arachidonylglycerol
Palmitylethanolamide
N
O
OH
H
CB272 279CB1 CB2CB1
Ki (nM)
58 145
AEAAEA
AEA
AEA
AEA
CB1/CB2
AEAAT
AEA
AEA
AA +
ethanolamine
biologicalactions
FAAH
extracellular space
DPPE
NAT
NAPE
PLD
DAG
2-AG
DAG-L2-AG
Cannabinoid Targets for Drug Discovery
Nature Neuroscience, Nature Neuroscience, Vol. 2, 4, 304-5 (1999)Vol. 2, 4, 304-5 (1999)
Retrograde Signaling & the Cannabinergic System
Purification of FAAH
• MW: 63 kDaMW: 63 kDa• pI: 6.2pI: 6.2
208208144144
8787
44.144.1
32.732.7
Inhibition of [3H]anandamide accumulation by AM 404 and AM403
Science, Vol. 277, 1094-97 (1997)
AM404
AM403
NH
O
OH
NH
O
OH
Pharmacological Tools
Cannabinergic Ligands
O
OH
O
NH
OH
AM 251AM 251
N
NN
I
N
O
Cl
Cl
H
Anandamides (AEA’s)Anandamides (AEA’s)
AM356AM356
1,5-Biarylpyrazoles1,5-Biarylpyrazoles
88-THC-THC
Aminoalkylindoles(AAI’s)Aminoalkylindoles(AAI’s)
Non-Classical (NCC’s)N
O
N
O
I OMe
AM630AM630
OH
OH
OH
Classical (CC’s)Classical (CC’s)CP55,940CP55,940
