The molecular basis of cannabinoid activity

Makriyannis, Alexandros; Rapaka, Rao S.

doi:10.1016/0024-3205(90)90147-j

Cited by 90 publications

(80 citation statements)

References 33 publications

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“…We might postulate that because of its amphipathic properties, CP-55,940 incorporates into biological membranes in its pharmacophoric conformation and assumes an orientation that allows all three hydroxyl groups to face the polar side of the bilayer, whereas in the bilayer, the cannabinoid ligand undergoes lateral diffusion and approaches the cannabinoid receptor in an orientation highly favorable for a productive collision with its binding site. This general hypothesis for the ligandmembrane-receptor systems has been discussed elsewhere (31,32,33) and is diagrammatically represented for CP-55,940 in Fig. 9.…”

Section: Figmentioning

confidence: 81%

The Conformational Properties of the Highly Selective Cannabinoid Receptor Ligand CP-55,940

Xie

Melvin

Makriyannis

1996

Journal of Biological Chemistry

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During a search for novel drugs possessing analgesic properties but devoid of the psychotropic effects of marijuana, a group of molecules designated as nonclassical cannabinoids was synthesized by Pfizer. Of these nonclassical cannabinoids CP-55,940 has received the most attention principally because it was used as the high affinity radioligand during the discovery and characterization of the G-protein-coupled cannabinoid receptor. In an effort to obtain information on the stereoelectronic requirements at the cannabinoid receptor active site, we have studied the conformational properties of CP-55,940 using a combination of solution NMR and computer modeling methods. Our data show that for the most energetically favored conformation, (i) the aromatic phenol ring is perpendicular to the cyclohexane ring, and the phenolic O-H bond is coplanar with the aromatic ring and points away from the cyclohexyl ring; ii) the dimethylheptyl chain adopts one of four preferred conformations in all of which the chain is almost perpendicular to the phenol ring; and iii) an intramolecular H-bond between the phenolic and hydroxypropyl groups allows all three hydroxyl groups of CP-55,940 to be oriented toward the upper face of the molecule. Such an orientation by the OH groups may be a characteristic requirement for cannabimimetic activity.The psychoactive effects of cannabinoids, particularly ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), 1 are well documented and offer a vexing target for new therapeutic drug discovery. Potential therapeutic applications include analgesia, sedation, attenuation of the nausea and vomiting due to cancer chemotherapy, appetite stimulation, decreasing intraocular pressure in glaucoma, certain motor or convulsant disorders, and concentration-time deficits (1, 2). A most probable site at which many of the pharmacological effects of cannabimimetics are induced is now thought to be the cannabinoid receptor (CB). This receptor type (CB1 and CB2 subtypes are described) is a subgroup of the G i -protein-coupled seven transmembrane spanning receptor superfamily (3). The CB1 receptor subtype is found predominately in brain (4, 5), whereas the CB2 receptor subtype is reported only in peripheral tissue (6).A series of compounds was designed, synthesized, and designated as nonclassical cannabinoids (NCCs), e.g. CP-55,940 in Fig. 1, which differ from classical cannabinoids by the absence of a tetrahydropyran ring, e.g. ⌬ 9 -THC and (Ϫ)9␤-OH-hexahydrocannabinol (7,8). Although the NCCs possess significant analgesic activity, there was sufficient data to indicate that these NCC molecules still exhibit the behavioral effects of the classical analogs (9, 10). Key pharmacophores for the NCC analogs include a phenolic hydroxyl (Ph-OH), an aliphatic side chain attached to the phenyl ring, and a cyclohexyl ring (Cring), all of which are also present in the natural cannabinoid ⌬ 9 -THC. Two additional pharmacophores, the northern and southern aliphatic hydroxyl groups, are not found in the natural cannabinoids but are present in mos...

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Section: Figmentioning

confidence: 81%

The Conformational Properties of the Highly Selective Cannabinoid Receptor Ligand CP-55,940

Xie

Melvin

Makriyannis

1996

Journal of Biological Chemistry

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“…For example, similar phenomena reflecting a large receptor reserve occur in the central nervous system, where very low levels of receptor occupancy cause profound behavioral effects (Gifford et al, 1999). Second, ligand binding sites for cannabinoid receptors are within the lipid bilayer of biological membranes (Makriyannis and Rapaka, 1990). Since AEA and THC are extremely hydrophobic and readily partition into membrane lipids, local agonist concentrations in close proximity to the receptor's binding site in the lipid bilayer may be considerably higher than in aqueous environments outside cells.…”

Section: Discussionmentioning

confidence: 99%

Evidence that anandamide‐signaling regulates human sperm functions required for fertilization

Schuel

Burkman

Lippes

et al. 2002

Molecular Reproduction Devel

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Ejaculated mammalian sperm require several hours exposure to secretions in female reproductive tracts, or incubation in appropriate culture medium in vitro, before acquiring the capacity to fertilize eggs. Arachidonylethanolamide (AEA), also known as anandamide, is a novel lipid-signal molecule that is an endogenous agonist (endocannabinoid) for cannabinoid receptors. We now report that AEA is present in human seminal plasma, mid-cycle oviductal fluid, and follicular fluid analyzed by high-performance liquid chromatography/mass spectrometry. Sperm are sequentially exposed to these reproductive fluids as they move from the vagina to the site of fertilization in the oviduct. Specific binding of the potent cannabinoid agonist [3 H]CP-55,940 to human sperm was saturable (K D 9.71 AE 1.04 nM), suggesting that they express cannabinoid receptors. R-methanandamide , a potent and metabolically stable AEA analog, and (À)D 9 tetrahydrocannabinol (THC), the major psychoactive constituent of Cannabis, modulated capacitation and fertilizing potential of human sperm in vitro. AM-356 elicited biphasic effects on the incidence of hyperactivated sperm motility (HA) between 1 and 6 hr of incubation: at (2.5 nM) it inhibited HA, while at (0.25 nM) it stimulated HA. Both AM-356 and THC inhibited morphological alterations over acrosomal caps between 2 and 6 hr (IC 50 5.9 AE 0.6 pM and 3.5 AE 1.5 nM, respectively). Sperm fertilizing capacity, measured in the Hemizona Assay, was reduced 50% by (1 nM) AM-356. These findings suggest that AEA-signaling may regulate sperm functions required for fertilization in human reproductive tracts, and imply that smoking of marijuana could impact these processes. This study has potential medical and public policy ramifications because of the incidence of marijuana abuse by adults in our society, previously documented reproductive effects of marijuana, and the ongoing debate about medicinal use of marijuana and cannabinoids.

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“…During the past 5 decades, many classical cannabinoids [1][2][3][4] including natural cannabis constituents, their metabolites, and other synthetic analogs have been synthesized and evaluated for their biological activities. A review 1,2,4,5 of the existing literature recognized 4 pharmacophores on the tricyclic terpenoid structure (Table 1) associated with cannabinergic activity: a phenolic hydroxyl at C1, a 5-to 8-atom-long side-chain at C3, a northern aliphatic hydroxyl at C9 or C11, and a southern aliphatic hydroxyl.…”

Section: Introductionmentioning

confidence: 99%

The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

Nikas

Grzybowska

Papahatjis

et al. 2004

AAPS J

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The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-∆ 8 -tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects. Conversely, 2-iodo substitution on the phenolic ring leads to a 2-fold reduction in affinity while iodo-substitution in the C1'-position of the side chain lowers the compound's affinity for CB1 by more than 8-fold. The pharmacophoric requirements resulting from halogen-substitution are explored using computer modeling methods.

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The molecular basis of cannabinoid activity

Cited by 90 publications

References 33 publications

The Conformational Properties of the Highly Selective Cannabinoid Receptor Ligand CP-55,940

The Conformational Properties of the Highly Selective Cannabinoid Receptor Ligand CP-55,940

Evidence that anandamide‐signaling regulates human sperm functions required for fertilization

The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

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