Affinage

CNR1

Cannabinoid receptor 1 · UniProt P21554

Length
472 aa
Mass
52.9 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNR1 encodes CB1, a class A G protein-coupled receptor that couples predominantly to Gi/o proteins to inhibit adenylyl cyclase, regulate Ca2+ and K+ channels, and stimulate MAPK cascades (p42/p44, p38, JNK), with regional and context-dependent flexibility in G protein selectivity (PMID:9336020, PMID:9974174, PMID:15308578, PMID:19620237). Signaling output is shaped by phosphorylation-dependent regulation: PKC phosphorylates S317 in the third intracellular loop to disrupt channel modulation (PMID:9526000), while GRK3/β-arrestin-2 acting on C-terminal sites S426/S430 drive homologous desensitization, a process governed by a receptor domain distinct from the extreme C-terminal region required for clathrin-mediated agonist-induced internalization (PMID:10428044, PMID:10234009, PMID:19620237). Structural studies define an orthosteric agonist pocket with F200(3.36)/W356(6.48) toggle-switch residues and TM2-dependent intracellular conformational changes that determine G protein activation efficacy, plus an extrahelical TM2-TM3-TM4 allosteric site where positive and negative modulators converge on TM2 rearrangement, and a cryptic pocket near D2.50 exploitable for peripherally restricted, G protein-biased analgesia (PMID:31659318, PMID:35637350, PMID:37160876, PMID:40044849). CB1 forms functional heteromers with β2-adrenoceptors, CB2, GPR55, and Smoothened, each reconfiguring downstream signaling and cross-regulation (PMID:20590567, PMID:22532560, PMID:23161546, PMID:31690747). Functionally, CB1 in hippocampal GABAergic interneurons inhibits GABA release to control inhibitory transmission, spatial memory, and mediated learning (PMID:30174119, PMID:26739712), mediates retrograde suppression of glutamatergic transmission (PMID:16527424), and acts during development in axonal pathfinding and parturition timing (PMID:18378465, PMID:18833324). It also operates in non-neuronal contexts including endothelial angiogenesis (PMID:21460248), mitochondrial ATP regulation and Drp1-dependent fission (PMID:33083022, PMID:29058339), and is expressed selectively in pancreatic delta-cells (PMID:18505678). Reduced CB1 transcription in striatum accompanies Huntington's disease progression in transgenic mice (PMID:15606779).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Established CB1 as a Gi/o-coupled GPCR whose juxtamembrane C-terminal region engages G proteins to inhibit adenylyl cyclase, regulate ion channels, and activate MAPK, defining the core transduction logic of the receptor.

    Evidence Pharmacological characterization, cell line expression, electrophysiology, and biochemical effector assays

    PMID:9336020 PMID:9974174

    Open questions at the time
    • Did not resolve atomic basis of G protein selectivity
    • Context-dependent Gs/Gq coupling not yet defined
  2. 1999 High

    Resolved that desensitization and internalization of CB1 are governed by distinct receptor domains — GRK3/β-arrestin-2 acting on C-terminal S426/S430 versus a separate distal C-terminal sequence for clathrin-mediated endocytosis — plus PKC-dependent S317 modulation, clarifying how receptor signaling is independently regulated.

    Evidence Site-directed mutagenesis, in vitro phosphorylation, oocyte and AtT-20 reconstitution, internalization assays, electrophysiology

    PMID:10234009 PMID:10428044 PMID:9526000

    Open questions at the time
    • Did not identify phosphatases driving recycling-coupled dephosphorylation
    • In vivo physiological consequences of each phosphosite not addressed
  3. 2000 Medium

    Showed CB1 drives cell migration through Gi-dependent MAPK activation independent of adenylyl cyclase inhibition, demonstrating effector-branch-specific physiological outputs.

    Evidence Boyden chamber migration assays in CB1-expressing HEK293 cells with pertussis toxin and MEK inhibitor dissection

    PMID:10871313

    Open questions at the time
    • Heterologous overexpression system only
    • Endogenous migratory contexts not tested
  4. 2006 High

    Genetically established CB1 as the obligatory mediator of cannabinoid-induced suppression of glutamatergic transmission in hippocampus, confirming its role in synaptic signaling in native tissue.

    Evidence Field recordings in hippocampal slices from two independent CB1 knockout lines

    PMID:16527424

    Open questions at the time
    • Did not localize the presynaptic source of receptor
    • Retrograde messenger identity not addressed here
  5. 2008 High

    Defined developmental, endocrine, and tissue-specific roles of CB1 — axonal pathfinding, parturition timing via CRH/steroid regulation, delta-cell-restricted islet expression, and trigeminovascular inhibition — broadening the receptor beyond classical neuromodulation.

    Evidence Cnr1 knockout/morpholino phenotyping, CRH antagonist rescue with steroid radioimmunoassay, islet immunofluorescence across three species, in vivo TCC electrophysiology

    PMID:17018694 PMID:18378465 PMID:18505678 PMID:18833324

    Open questions at the time
    • Delta-cell CB1 signaling output on hormone secretion not functionally tested
    • Cell-autonomous versus systemic contributions to parturition unresolved
  6. 2012 High

    Demonstrated that CB1 physically heteromerizes with β2-adrenoceptors, CB2, and GPR55, reconfiguring constitutive activity, surface expression, and ERK/Akt/NFAT signaling, establishing receptor-receptor crosstalk as a layer of CB1 regulation.

    Evidence BRET/FRET, reciprocal co-immunoprecipitation, transcription reporter and phosphorylation assays in heterologous cells, native brain tissue, and primary ocular cells

    PMID:20590567 PMID:22532560 PMID:23161546

    Open questions at the time
    • Stoichiometry and structural interface of heteromers undefined
    • Physiological prevalence of each heteromer in vivo not quantified
  7. 2018 High

    Showed CB1 in hippocampal GABAergic neurons is necessary and sufficient for inhibitory transmission control and specific forms of learning, pinpointing a defined neural circuit substrate for CB1 cognitive function.

    Evidence Cell-type-specific conditional knockout and rescue, chemogenetics, sensory preconditioning behavior, IPSC and plasticity recordings

    PMID:26739712 PMID:30174119

    Open questions at the time
    • Molecular mechanism of activity-dependent CB1 upregulation not defined
    • Generalizability beyond hippocampal GABAergic neurons untested
  8. 2019 High

    Crystallography revealed an extrahelical allosteric site overlapping a cholesterol interaction site and captured an intermediate receptor state, providing the structural basis for allosteric modulation of CB1.

    Evidence X-ray crystallography of CB1 ternary complex with NAM ORG27569 and agonist CP55940

    PMID:31659318

    Open questions at the time
    • Single allosteric modulator captured
    • Did not yet define the mechanistic step linking allosteric site to activation
  9. 2022 High

    Established that positive and negative allosteric modulators binding the TM2-TM3-TM4 surface converge on a shared TM2 rearrangement that gates activation, unifying the mechanism of bidirectional allosteric control.

    Evidence Crystallography, cryo-EM with PAM ZCZ011, biased/unbiased MD simulations, mutagenesis, signaling assays

    PMID:35637350

    Open questions at the time
    • Kinetics of TM2 transition not quantified
    • Endogenous regulators of this site unknown
  10. 2023 High

    Active-state cryo-EM defined ligand-driven TM2 conformational changes unique to CB1 and toggle-switch residues F200/W356 as determinants of G protein activation efficacy, linking ligand chemistry to coupling output.

    Evidence Cryo-EM of agonist-CB1-G protein complex, docking, MD, mutagenesis, signaling assays

    PMID:37160876

    Open questions at the time
    • Arrestin-bound active state not resolved here
    • Determinants of biased signaling not yet structurally mapped
  11. 2025 High

    Identified a cryptic D2.50 pocket targetable to achieve peripherally restricted, G protein-biased agonism with separation of analgesia from central side effects, demonstrating actionable structure-guided pharmacology.

    Evidence MD-guided design, structure determination, biased signaling pharmacology, three in vivo mouse pain models, PK studies

    PMID:40044849

    Open questions at the time
    • Long-term safety and clinical translation untested
    • Endogenous role of this cryptic pocket unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CB1 subcellular pools — plasma membrane, mitochondria, and heteromeric assemblies — are coordinated to produce distinct physiological outputs in a given cell remains unresolved.
  • Mechanism targeting CB1 to mitochondria undefined
  • Quantitative partitioning between signaling pools unknown
  • Integration of heteromer-specific signaling in native tissue not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
ADRB2ARRB2CB2GPR55GRK3SMO

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CB1 receptor is a G protein-coupled receptor coupled to G proteins; it inhibits adenylyl cyclase and regulates ion channels in the CNS, and is activated by cannabinoid ligands including endogenous agonists. Pharmacological characterization, binding studies, effector system assays Pharmacology & therapeutics High 9336020
1998 CB1 receptor couples to Gi/o proteins to inhibit adenylate cyclase, regulate Ca2+ channels and K+ channels, and stimulate the MAP kinase pathway; the juxtamembrane C-terminal region extending from helix VII is proposed to activate G proteins. Expression in cell lines, electrophysiology, biochemical effector assays Neurobiology of disease High 9974174
1998 Protein kinase C (PKC) phosphorylates a single serine (S317) in the third intracellular loop of CB1, and this phosphorylation disrupts CB1-mediated modulation of potassium and calcium channels; mutating S317 to alanine eliminated PKC-mediated disruption without affecting basal channel modulation. Site-directed mutagenesis, PKC phosphorylation of fusion protein, electrophysiology in AtT-20 cells transfected with rat CB1 The Journal of neuroscience High 9526000
1999 CB1 receptors are rapidly internalized following agonist binding via clathrin-coated pits; internalization does not require activated Gα subunits; a region of the extreme carboxy terminus (last 14 residues) is necessary for internalization. Recycling of sequestered receptor requires endosomal acidification and dephosphorylation. Pharmacological internalization assays with hypertonic sucrose blockade, C-terminal truncation mutants, new protein synthesis inhibition Journal of neurochemistry High 10428044
1999 GRK3 and β-arrestin 2 mediate homologous CB1 receptor desensitization; residues within the C-terminal tail (418–439), specifically phosphorylation sites S426 and S430, are required for GRK3/β-arrestin-dependent desensitization but not for internalization. CB1 desensitization and internalization are thus governed by distinct receptor domains. Xenopus oocyte expression system with GRK3/β-arrestin co-expression, K+ conductance electrophysiology, site-directed mutagenesis (S426A, S430A), AtT-20 cell internalization assays The Journal of neuroscience High 10234009
2000 CB1 receptor activation mediates cell migration (chemotaxis and chemokinesis) via pertussis toxin-sensitive Gi proteins; this migratory response depends on MAP kinase activation but not on adenylyl cyclase inhibition. Modified Boyden chamber migration assay in HEK293 cells stably expressing human CB1, pertussis toxin treatment, PD098059 (MEK inhibitor) treatment, SR141716A antagonism The Journal of pharmacology and experimental therapeutics Medium 10871313
2004 CB1 receptor signal transduction efficacy depends on coupling to Gi/o proteins, with evidence for regional differences in G protein selectivity in brain; CB1 can also interact with Gs or Gq in some cellular contexts. [35S]GTPγS binding assays, adenylyl cyclase assays, brain regional comparisons British journal of pharmacology Medium 15308578
2009 CB1R signals primarily through Gi/o proteins to inhibit adenylyl cyclase and regulate ion channels; it also activates MAPK pathways (p42/p44, p38, JNK) via Gi/o; activated/phosphorylated CB1R associates with β-arrestins, forming signaling complexes; CB1R can form homo- and heterodimers/oligomers with altered pharmacological properties. Biochemical assays, co-immunoprecipitation, resonance energy transfer approaches, functional signaling assays Journal of molecular endocrinology Medium 19620237
2010 CB1 receptor physically interacts with β2-adrenoceptors as demonstrated by BRET; co-expression of β2-adrenoceptors reduces CB1 constitutive activity, increases CB1 cell-surface expression, enhances Gαi-dependent ERK phosphorylation, and decreases non-Gαi-mediated CREB phosphorylation. These interactions were confirmed in primary human trabecular meshwork cells endogenously co-expressing both receptors. Bioluminescence resonance energy transfer (BRET), co-expression in HEK293H cells, ERK and CREB signaling assays, primary human ocular cell experiments British journal of pharmacology High 20590567
2012 CB1 and CB2 receptors form functional heteromers in transfected neuronal cells and in rat brain (pineal gland, nucleus accumbens, globus pallidus); within CB1-CB2 heteromers, co-activation produces negative cross-talk in Akt phosphorylation and neurite outgrowth; CB1 antagonists can block CB2 agonist effects and vice versa (bidirectional cross-antagonism). Biophysical (BRET/FRET) and biochemical (co-immunoprecipitation) approaches in transfected neuronal cells and rat brain tissue; Akt phosphorylation and neurite outgrowth assays The Journal of biological chemistry High 22532560
2012 CB1 receptor co-expression with GPR55 leads to heteromer formation; this heteromer inhibits GPR55-mediated NFAT and SRE transcription factor activation and ERK1/2 activation; conversely, GPR55 presence enhances CB1R-mediated ERK1/2 and NFAT activation. Internalization of both receptors is not affected by heteromerization. Co-immunoprecipitation, BRET, transcription factor reporter assays (NFAT, SRE), ERK1/2 phosphorylation assays in HEK293 cells The Journal of biological chemistry Medium 23161546
2013 CB1 receptor activation by AEA or ACEA (CB1-specific agonist) enhances neuronal differentiation of neural stem cells but not astrocyte or oligodendrocyte differentiation; CB1 activation causes long-term inhibition of ERK1/2 signaling, and pharmacological inhibition of ERK1/2 recapitulates the pro-neuronal differentiation effect. Pharmacological activation/antagonism in mouse NSCs, RT-PCR, Western blot, morphometric analysis, gene array profiling, ERK1/2 pathway inhibition PloS one Medium 23372698
2008 Loss of CB1 function (pharmacological or genetic, Cnr1 knockout) in mice causes defects in axonal growth and fasciculation during embryonic development; CB1 is required for normal axonal pathfinding in vivo. CB1 pharmacological inhibition, morpholino knockdown in zebrafish, loss-of-function phenotype analysis (axon pathfinding/fasciculation) Molecular and cellular neurosciences Medium 18378465
2008 Genetic inactivation of CB1 (Cnr1 knockout), but not CB2, induces preterm birth in mice; CB1 deficiency alters progesterone/estrogen ratios before parturition; CB1 inactivation causes aberrant CRH and corticosterone secretion, and a CRH antagonist restores normal parturition timing in Cnr1 null mice. Cnr1 and Cnr2 targeted deletion mouse models, pharmacological inactivation, radioimmunoassay for steroid hormones, CRH antagonist rescue PloS one High 18833324
2006 CB1 receptor mediates cannabinoid-induced suppression of glutamatergic (Schaffer collateral-CA1) synaptic transmission in the hippocampus; CB1 knockout mice of two independent lines show no cannabinoid-mediated suppression at this synapse. Extracellular field recordings in hippocampal slices from two independently generated CB1-/- mouse lines vs. wild-type controls Neuroscience High 16527424
2011 CB1 receptor signaling promotes angiogenesis; siRNA-mediated knockdown or pharmacological antagonism of CB1 inhibits bFGF-induced endothelial proliferation, migration, and capillary-like tube formation via ERK, Akt, FAK, JNK, Rho, and MMP-2 pathways; CB1 blockade also inhibits neovascular growth in vivo (rabbit cornea assay and mouse retinopathy model). siRNA knockdown, pharmacological antagonism, in vitro endothelial proliferation/migration/tube formation assays, in vivo corneal and retinal neovascularization models Blood High 21460248
2019 Crystal structure of CB1 bound to the negative allosteric modulator (NAM) ORG27569 and agonist CP55940 reveals that ORG27569 binds to an extrahelical site within the inner leaflet of the membrane overlapping with a conserved cholesterol interaction site; the ternary complex captures an intermediate receptor state where aromatic residues at the base of the agonist-binding pocket adopt inactive conformation despite orthosteric pocket contraction. X-ray crystallography of CB1 ternary complex (NAM + agonist) Nature chemical biology High 31659318
2022 The positive allosteric modulator (PAM) ZCZ011 binds to an extrahelical site at the TM2-TM3-TM4 surface of CB1; TM2 rearrangement is critical for allosteric signal propagation; ZCZ011 promotes TM2 rearrangement favoring receptor activation, while the NAM ORG27569 (also binding TM2-TM3-TM4) impedes TM2 rearrangement. Both allosteric modulators converge on the same TM2 rearrangement mechanism. X-ray crystallography, cryo-EM structures of CB1 with PAM ZCZ011, unbiased and biased molecular dynamics simulations, site-directed mutagenesis, functional signaling assays Nature chemical biology High 35637350
2023 Cryo-EM structure of CB1 bound to an endocannabinoid analog (AMG315) in an active signaling complex reveals ligand binding pocket details; ligand interactions with TM2 residues drive conformational changes on the intracellular side of TM2 that are unique to CB1 and are a determinant of G protein activation efficacy; the 'toggle switch' residues F200(3.36) and W356(6.48) are functionally important for activation. Cryo-EM structure determination of agonist-CB1-G protein complex, molecular docking, molecular dynamics simulations, mutagenesis, signaling assays Nature communications High 37160876
2025 A cryptic pocket in CB1 (identified by molecular dynamics simulations, leading to D2.50) can be targeted by positively charged agonist derivatives to achieve peripheral restriction and dampened arrestin recruitment; the lead ligand VIP36 occupying this cryptic pocket shows 100-fold dose separation between peripheral analgesic efficacy and centrally mediated side effects in mouse pain models, with limited tolerance development. Computational MD simulation-guided design, structure determination, pharmacological assays for G protein vs arrestin signaling bias, in vivo mouse pain models (three models), PK studies Nature High 40044849
2018 CB1 receptors specifically in hippocampal GABAergic neurons are necessary and sufficient for mediated (incidental) learning; deletion and re-expression of CB1R in hippocampal GABAergic neurons abolishes and rescues mediated learning respectively; paired sensory cues induce protein synthesis-dependent upregulation of hippocampal CB1R expression and facilitate long-term plasticity at inhibitory synapses. Cell-type-specific CB1R deletion and re-expression (conditional KO and rescue), sensory preconditioning behavioral paradigm, chemogenetic manipulation of hippocampal GABAergic neurons, electrophysiology for synaptic plasticity Neuron High 30174119
2016 CB1 receptors in hippocampal GABAergic interneurons inhibit GABA release; deletion of CB1R from GABAergic neurons enhances frequency and kinetics of spontaneous IPSCs in CA1 pyramidal neurons and impairs acquisition of spatial memory and novel object recognition, without affecting tonic inhibition, paired-pulse facilitation, or LTP. Cell-type-specific CB1R knockout in GABAergic neurons, patch clamp and field potential recordings, behavioral cognitive testing Pflugers Archiv High 26739712
2004 Expression of CB1 mRNA in the striatum of Huntington's disease transgenic mice (R6/1, R6/2) is progressively reduced due to decreased transcription; the CB1 gene has two exons separated by an 18.4 kb intron with a GC-rich promoter; the progressive decline is caused by altered transcription factor activity due to mutant huntingtin expression. RT-PCR, promoter analysis, transcription start site mapping, comparison of HD transgenic vs wild-type mice at multiple ages European journal of biochemistry Medium 15606779
2019 CB1 receptor forms heteromers with Smoothened (Smo), the Hedgehog pathway transducer, as demonstrated by proximity ligation assay; cannabinoids reduce Shh signaling by inhibiting Smo, and a CB1 receptor antagonist attenuates cannabinoid-induced birth defects; CB1-Smo heteromers suggest allosteric CB1-Smo interaction. Proximity ligation assay (PLA) in mouse/zebrafish embryo models, CB1 antagonist rescue, Shh pathway reporter assays Scientific reports Medium 31690747
2020 CB1 receptor activation (ACEA) protects against brain ischemia/reperfusion injury by inhibiting mitochondrial fission via Drp1; CB1 agonist ACEA reduced OGD/R-induced neuronal injury and MCAO-induced infarct volume; neuroprotective effects were blocked by CB1 antagonist AM251 or Drp1 upregulation, establishing a CB1-Drp1 pathway. OGD/R model in neuronal cells, MCAO rat model, co-administration of CB1 antagonist AM251 and Drp1 overexpression, mitochondrial fission and apoptosis assays Cell death discovery Medium 33083022
2022 CB1 receptor activation in human bone marrow MSCs enhances osteogenic differentiation and rescues mitochondrial energy metabolism (OCR and mitochondrial membrane potential) impaired by inflammatory cytokines; CB1 activation promotes JNK and p38 MAPK signaling and inhibits ERK1/2; this effect was linked to enhanced mitochondrial electron transport chain activity. CB1 agonist/antagonist treatment, CB1 knockdown, Seahorse metabolic analysis, JC-10 MMP assay, Western blot for MAPK pathways, osteogenic differentiation assays Stem cell research & therapy Medium 35063024
2008 CB1 receptor is expressed specifically in pancreatic delta-cells (somatostatin-positive) in mouse, rat, and human islets; CB1 is not detected in alpha-, beta-, or PP-cells of islets; monoacylglycerol lipase (MAGL) is expressed in delta-cells and FAAH in alpha-cells. Confocal immunofluorescence microscopy with co-localization for somatostatin, insulin, glucagon markers; RT-PCR in islets and cell lines Biochemical and biophysical research communications Medium 18505678
2017 CB1 receptors are functionally present within brain mitochondria (mtCB1); acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. Mitochondrial fractionation, functional assays of mitochondrial ATP production, synaptic transmission measurements, memory behavioral tests BioEssays Medium 29058339
2008 CB1 receptor activation inhibits trigeminovascular neuronal responses to A- and C-fiber inputs from the dura mater; this inhibition is blocked by CB1 antagonist SR141716 but not CB2 antagonist AM630, establishing CB1-mediated inhibition of trigeminocervical complex neurons. Extracellular electrophysiology of TCC neurons in rats, cannabinoid agonist WIN55,212 and anandamide treatment with selective antagonists SR141716 and AM630 The Journal of pharmacology and experimental therapeutics Medium 17018694
2008 CB1 receptor mRNA expression in the Fallopian tube shows temporal (luteal > follicular) variation likely regulated by progesterone; CB1 mRNA is attenuated in Fallopian tube and decidua of women with ectopic pregnancy, suggesting that CB1 signaling regulates embryo transport in the human oviduct. RT-PCR and immunohistochemistry of timed Fallopian tube biopsies from women with and without ectopic pregnancy PloS one Low 19093002

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacology & therapeutics 1199 9336020
2004 Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life sciences 358 15670612
2008 Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures--a short review. Pharmacology, biochemistry, and behavior 332 18584858
2017 CB1 and CB2 Receptor Pharmacology. Advances in pharmacology (San Diego, Calif.) 262 28826534
2009 Signal transduction of the CB1 cannabinoid receptor. Journal of molecular endocrinology 259 19620237
1999 Internalization and recycling of the CB1 cannabinoid receptor. Journal of neurochemistry 244 10428044
2010 CB(1) cannabinoid receptors and their associated proteins. Current medicinal chemistry 225 20166926
1999 Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. The Journal of neuroscience : the official journal of the Society for Neuroscience 209 10234009
2012 Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. The Journal of biological chemistry 192 22532560
2002 CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Molecular psychiatry 166 12082570
2019 Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. Nature chemical biology 150 31659318
1997 Cannabinoid receptor gene (CNR1): association with i.v. drug use. Molecular psychiatry 138 9106242
2003 CB1 cannabinoid receptor signalling in Parkinson's disease. Current opinion in pharmacology 131 12550742
1998 Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 127 9526000
2008 The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation. Molecular and cellular neurosciences 119 18378465
2006 The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus. Neuroscience 111 16527424
2010 Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression. Pharmacological research 106 20080186
2014 Stress regulates endocannabinoid-CB1 receptor signaling. Seminars in immunology 103 24882055
2009 Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 99 20010552
2012 Associations between cannabinoid receptor-1 (CNR1) variation and hippocampus and amygdala volumes in heavy cannabis users. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 98 22669173
2008 Specific detection of CB1 receptors; cannabinoid CB1 receptor antibodies are not all created equal! Journal of neuroscience methods 94 18406468
2005 CB1 receptor antagonists for the treatment of nicotine addiction. Pharmacology, biochemistry, and behavior 94 15935455
2019 Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction. Scientific reports 89 31690747
2006 Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. International journal of obesity (2005) 88 16570100
2006 Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces. The European journal of neuroscience 87 16623851
2006 Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. The Journal of pharmacology and experimental therapeutics 87 17018694
2004 Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington's disease transgenic mice. European journal of biochemistry 87 15606779
2005 Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1). The pharmacogenomics journal 86 15668727
2021 CB1 Cannabinoid Receptor Signaling and Biased Signaling. Molecules (Basel, Switzerland) 85 34500853
2008 Cannabis reinforcement and dependence: role of the cannabinoid CB1 receptor. Addiction biology 85 18279497
2005 Rimonabant--a selective CB1 antagonist. The Annals of pharmacotherapy 85 15755787
2008 Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 83 18213623
2013 Peripherally restricted CB1 receptor blockers. Bioorganic & medicinal chemistry letters 82 23902803
2022 Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1. Nature chemical biology 81 35637350
2016 Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor. Medicinal research reviews 81 27879006
2012 The cannabinoid receptor CB1 modulates the signaling properties of the lysophosphatidylinositol receptor GPR55. The Journal of biological chemistry 81 23161546
2008 The role of CB1 receptors in psychostimulant addiction. Addiction biology 81 18482432
2012 Endocannabinoids via CB₁ receptors act as neurogenic niche cues during cortical development. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 78 23108542
2013 Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PloS one 74 23372698
2012 The role of CB1 in immune modulation by cannabinoids. Pharmacology & therapeutics 74 23261520
2011 Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis. Blood 73 21460248
2013 CB1 receptor signaling regulates social anxiety and memory. Genes, brain, and behavior 72 23647582
2010 Physical and functional interaction between CB1 cannabinoid receptors and beta2-adrenoceptors. British journal of pharmacology 72 20590567
2015 Astroglial type-1 cannabinoid receptor (CB1): A new player in the tripartite synapse. Neuroscience 71 25967266
2008 CB(1) receptor antagonism: biological basis for metabolic effects. Drug discovery today 71 18824122
2008 Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 68 18186055
1999 A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene. Molecular and cellular probes 67 10441206
2020 Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia. Translational psychiatry 66 32433545
2019 Structural Insights into CB1 Receptor Biased Signaling. International journal of molecular sciences 65 31013934
2017 The CB1 Receptor as the Cornerstone of Exostasis. Neuron 65 28334603
2008 CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy. PloS one 63 19093002
2009 Promoter variants of the cannabinoid receptor 1 gene (CNR1) in interaction with 5-HTTLPR affect the anxious phenotype. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 62 19725030
2017 Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology 61 28527758
2000 Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatric genetics 61 11204352
2014 Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert opinion on investigational drugs 60 24836296
2005 CB1 cannabinoid receptor ligands. Mini reviews in medicinal chemistry 59 16026309
2016 Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation? Annual review of neuroscience 58 27023732
2011 CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta-analysis. Addiction biology 58 20192949
1999 Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life sciences 58 10462060
2010 Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 57 20218784
2007 The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 57 17669634
1998 The CB1 cannabinoid receptor in the brain. Neurobiology of disease 57 9974174
2017 The role of CB1 in intestinal permeability and inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 56 28404744
2008 Loss of cannabinoid receptor CB1 induces preterm birth. PloS one 56 18833324
2012 CB1 receptor antagonists: new discoveries leading to new perspectives. Acta physiologica (Oxford, England) 55 22463610
2004 Efficacy in CB1 receptor-mediated signal transduction. British journal of pharmacology 55 15308578
2008 Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology 53 18468662
2013 CB1 cannabinoid receptor-mediated aggressive behavior. Neuropharmacology 51 23916480
2009 Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects. Genes, brain, and behavior 51 19659925
1997 Association between the cannabinoid receptor gene (CNR1) and the P300 event-related potential. Molecular psychiatry 50 9106243
2023 Structural basis for activation of CB1 by an endocannabinoid analog. Nature communications 48 37160876
2004 Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors. Annals of the New York Academy of Sciences 47 15542757
2000 CB1 cannabinoid receptor-mediated cell migration. The Journal of pharmacology and experimental therapeutics 46 10871313
2007 No association of CNR1 gene variations with susceptibility to schizophrenia. Neuroscience letters 43 17881126
2007 Expression of cannabinoid CB1 receptors in models of diabetic neuropathy. The Journal of pharmacology and experimental therapeutics 41 17702901
2009 Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans. Metabolism: clinical and experimental 39 19919870
2018 Hippocampal CB1 Receptors Control Incidental Associations. Neuron 37 30174119
2008 The cannabinoid CB1 receptor is expressed in pancreatic delta-cells. Biochemical and biophysical research communications 37 18505678
2008 Development of radioligands for in vivo imaging of type 1 cannabinoid receptors (CB1) in human brain. Current pharmaceutical design 37 19075713
2017 Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition. Aging cell 36 28752643
2017 Linking Mitochondria and Synaptic Transmission: The CB1 Receptor. BioEssays : news and reviews in molecular, cellular and developmental biology 36 29058339
2020 Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs. Biomolecules 35 32512776
2007 No evidence for an involvement of variants in the cannabinoid receptor gene (CNR1) in obesity in German children and adolescents. Molecular genetics and metabolism 35 17292652
2020 Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation. Molecules (Basel, Switzerland) 34 31968549
2015 CB1 receptors modulate affective behaviour induced by neuropathic pain. Brain research bulletin 34 25863168
2005 Development and expression of neuropathic pain in CB1 knockout mice. Neuropharmacology 34 16169563
2015 Cannabinoid CB1 receptors mediate the effects of dipyrone. Clinical and experimental pharmacology & physiology 32 25430877
2020 Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1-Drp1 pathway. Cell death discovery 31 33083022
2009 Variants in the CNR1 and the FAAH genes and adiposity traits in the community. Obesity (Silver Spring, Md.) 31 19165169
2022 The cannabinoid receptor I (CB1) enhanced the osteogenic differentiation of BMSCs by rescue impaired mitochondrial metabolism function under inflammatory condition. Stem cell research & therapy 30 35063024
2011 Further evidence for association of polymorphisms in the CNR1 gene with cocaine addiction: confirmation in an independent sample and meta-analysis. Addiction biology 30 21790903
2014 Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors. PloS one 28 24950219
2019 The association of endocannabinoid receptor genes (CNR1 and CNR2) polymorphisms with depression: A meta-analysis. Medicine 27 31725603
2025 A cryptic pocket in CB1 drives peripheral and functional selectivity. Nature 26 40044849
2016 Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons. Pflugers Archiv : European journal of physiology 26 26739712
2012 MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse. Psychological medicine 26 22850347
2001 The cannabinoid receptor gene (CNR1) is not affected in German i.v. drug users. Addiction biology 26 11341859
2013 CNR1 gene and risk of the metabolic syndrome in patients with schizophrenia. Journal of clinical psychopharmacology 25 23422373
2010 Understanding functional residues of the cannabinoid CB1. Current topics in medicinal chemistry 25 20370713
2008 Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives. Chemical record (New York, N.Y.) 25 18563799

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