The cannabinoid receptor: biochemical, anatomical and behavioral characterization

Howlett, Allyn C.; Bidaut‐Russell, Michelle; Devane, William A.; Melvin, Lawrence S.; Johnson, M. R.; Herkenham, Miles

doi:10.1016/0166-2236(90)90124-s

Cited by 285 publications

(162 citation statements)

References 18 publications

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“…For a molecule like CP-55,940 with several flexible substituents other than the hydroxypropyl chain, the dynamics calculations would have to sample too many conformations. Therefore, we imposed restraints on the torsional angles of certain regions, such as the DMH chain (except for the two dihedral angles adjacent to the A-ring, 3 and 4 , in Table III), the C-ring, and the Ph-OH, which we found to be similar to that of its earlier studied congener CP-47,497. To avoid a formation of cis or gauche segments in the DMH side chain and to evade possible chair-boat interconversions in the cyclohexyl ring, a torsional restraint of 100 kcal/rad 2 was added to the corresponding torsion angles in those regions.…”

Section: Methodssupporting

confidence: 49%

“…The chemical shift values (Table I) and approximated J values were then used as the starting point for an iterative simulation of the subspectra thus allowing us to refine 2 J and 3 J values (Table II). 3 J values so obtained were then incorporated into the Karplus equation (18) as we have described elsewhere (13,19) to calculate the corresponding dihedral angles (Table II), which indicated a typical chair conformation of the C-ring.…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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: Methodssupporting

confidence: 49%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…The presence of mood fluctuations seems to have some relationship to the changes in motor symptoms in PD patients, with major depression symptoms in 'off' periods and fewer symptoms in 'on' periods. 4,15 CB1 cannabinoid receptors are widely expressed in the brain, 16 mainly in the neocortex, hippocampus, basal ganglia and cerebellum. 17 Cannabinoid receptors are codified by the CNR1 gene, located in chromosome 6q14-q15; 18 cDNA coding for CB1 was cloned by Gerard et al 19 in stem cells of the human brain.…”

Section: Introductionmentioning

confidence: 99%

Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1)

et al. 2005

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Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P ¼ 0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.

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“…Su efecto es inhibido por la yohimbina (antagonista ␣-2-adrenérgico) y el propanolol (antagonista ␤-adrenérgico). Asimismo, carece de afinidad por receptores CB1 o CB2, lo cual nos sugiere que su efecto hipotensor ocular podría estar mediado por vías distintas a las dependientes de los principales receptores de cannabinoides 41 .…”

Section: Cannabinoides Y Presión Intraocularunclassified

Aplicaciones de los cannabinoides en glaucoma

Pinar-Sueiro

Rodrı́guez-Puertas

Vecino

2011

Archivos de la Sociedad Española de Oftalmología

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Introducción: El glaucoma es una neuropatía óptica lentamente progresiva que constituye una de las principales causas de ceguera legal en el mundo. Actualmente existe un limitado grupo de fármacos tópicos para su manejo médico, siendo necesario enfocar la investigación hacia nuevos horizontes terapéuticos como el potencialmente útil grupo de los agonistas de cannabinoides.Objetivo: Revisar a través de la literatura científica actual, los efectos beneficiosos a través de distintas vías de administración de los cannabinoides para la neuropatía óptica glaucomatosa.Desarrollo: Los receptores de cannabinoides han demostrado una amplia expresión en los tejidos oculares implicados en la regulación de la tensión ocular, así como en las capas internas de la retina. Mediante la activación de receptores específicos CB1, CB2 y vías aún no bien conocidas, los agonistas de cannabinoides han demostrado un claro efecto hipotensor ocular, así como un probado efecto neuroprotector sobre las células ganglionares de la retina en estudios experimentales.Conclusiones: Algunos cannabinoides (WIN 55212-2, anandamida) han demostrado a nivel experimental actuar como «fármacos ideales» en el manejo del glaucoma, al presentar buena tolerancia tras su aplicación tópica, reducir de forma eficaz la presión intraocular, y presentar un probado carácter neuroprotector sobre las células ganglionares de la retina.Se deben realizar más estudios sobre su seguridad y ensayos clínicos para poder examinar la utilidad de estos fármacos en el tratamiento del glaucoma en nuestra clínica diaria.

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The cannabinoid receptor: biochemical, anatomical and behavioral characterization

Cited by 285 publications

References 18 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

Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1)

Aplicaciones de los cannabinoides en glaucoma

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