AM-251

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H21Cl2IN4O
Molecular Weight	555.239
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=C(N(N=C1C(=O)NN2CCCCC2)C3=CC=C(Cl)C=C3Cl)C4=CC=C(I)C=C4

InChI

InChIKey=BUZAJRPLUGXRAB-UHFFFAOYSA-N

InChI=1S/C22H21Cl2IN4O/c1-14-20(22(30)27-28-11-3-2-4-12-28)26-29(19-10-7-16(23)13-18(19)24)21(14)15-5-8-17(25)9-6-15/h5-10,13H,2-4,11-12H2,1H3,(H,27,30)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/9335234 | https://www.ncbi.nlm.nih.gov/pubmed/14665975 | https://www.ncbi.nlm.nih.gov/pubmed/23932644

AM-251 is a 123I radioisotope and potent CB1 receptor antagonist derivative of the CB1 cannabinoid receptor inverse agonist SR141716A, presenting a radioprobe for in vivo binding studies at the CB1 receptor with a higher affinity (Ki = 7.49 nM) for CB1 than the parent compound (Ki = 11.5 nM). AM-251 has been employed in competitive binding studies to identify CB1 affinity of different cannabimimetic agonists in vivo. AM-251 is also a potent activator of the GPR55 receptor. Daily injection of AM-251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM-251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. AM-251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cannabinoid CB1 receptor 85 Target ID: CHEMBL218 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10052983 \| https://www.ncbi.nlm.nih.gov/pubmed/19338772 \| https://www.ncbi.nlm.nih.gov/pubmed/18333607	Antagonist 2778		3.5 nM [IC50]
G-protein coupled receptor 55 6 Target ID: CHEMBL1075322 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17876302	Agonist 2678		39.0 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Obesity 203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14665975 https://www.ncbi.nlm.nih.gov/pubmed/23932644 https://www.ncbi.nlm.nih.gov/pubmed/23033907 https://www.ncbi.nlm.nih.gov/pubmed/21395869	Primary		Preclinical	Unknown Approved Use Unknown
Pain 614 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25188001 https://www.ncbi.nlm.nih.gov/pubmed/21645531 http://www.coalition4paintreatment.com/1/26/552/intrathecal-palmitoylethanolamide-and-am251-and-spinal-cord-il1-beta-expression-details	Primary		Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
		252159962
Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists.	1999 Feb 25	10052983
The cannabinoids R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU-210), 2-O-arachidonoylglycerylether (HU-310) and arachidonyl-2-chloroethylamide (ACEA) increase isoflurane provoked sleep duration by activation of cannabinoids 1 (CB1)-receptors in mice.	2002 Jul 5	12095655
Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251.	2002 Jun	12095072
Effect of (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55,940) on intracellular Ca2+ levels in human osteosarcoma cells.	2002 Sep 30	12817711
Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide.	2003 Jan 15	12509806
Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice.	2004 Aug	15266010
The effect of am 251, a cannabinoid CB1 receptor antagonist, on food intake in rats.	2004 Sep-Oct	15747698
Transient receptor potential vanilloid subtype 1 mediates cell death of mesencephalic dopaminergic neurons in vivo and in vitro.	2005 Jan 19	15659603
Retrograde endocannabinoid signaling in a postsynaptic neuron/synaptic bouton preparation from basolateral amygdala.	2005 Jun 29	15987949
Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors.	2005 Oct	16100529
Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids.	2005 Oct 19	16237178
Activation of cannabinoid CB1 receptors induces glucose intolerance in rats.	2006 Feb 15	16423347
Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism.	2006 Mar 20	16500647
Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice.	2007 Aug 13	17553486
Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.	2007 Dec	17953671
The orphan receptor GPR55 is a novel cannabinoid receptor.	2007 Dec	17876302
Endocannabinoids mediate muscarine-induced synaptic depression at the vertebrate neuromuscular junction.	2007 Mar	17408433
2-Arachidonylglyceryl ether and abnormal cannabidiol-induced vascular smooth muscle relaxation in rabbit pulmonary arteries via receptor-pertussis toxin sensitive G proteins-ERK1/2 signaling.	2007 Mar 22	17292352
Cannabinoids ameliorate pain and reduce disease pathology in cerulein-induced acute pancreatitis.	2007 May	17484889
CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception.	2007 May-Jun	17439413
Differential sensitivity of GABA A receptor-mediated IPSCs to cannabinoids in hippocampal slices from adolescent and adult rats.	2007 Sep	17634345
CB1-cannabinoid receptors are involved in the modulation of non-synaptic [3H]serotonin release from the rat hippocampus.	2008 Jan	17719142
Methanandamide allosterically inhibits in vivo the function of peripheral nicotinic acetylcholine receptors containing the alpha 7-subunit.	2008 Sep	18567834
Effect of cannabinoids upon the uptake of folic acid by BeWo cells.	2009	19145103
Endogenous cannabinoids induce fever through the activation of CB1 receptors.	2009 Aug	19681872
Signaling pathways from cannabinoid receptor-1 activation to inhibition of N-methyl-D-aspartic acid mediated calcium influx and neurotoxicity in dorsal root ganglion neurons.	2009 Dec	19752241
Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma.	2009 Jul	19509271
Potential anxiolytic- and antidepressant-like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents.	2009 Jul	19422370
Novel mGluR- and CB1R-independent suppression of GABA release caused by a contaminant of the group I metabotropic glutamate receptor agonist, DHPG.	2009 Jul 1	19568435
Comparison between spontaneous and kainate-induced gamma oscillations in the mouse hippocampus in vitro.	2009 Jun	19490088
Neurochemical evidence that stimulation of CB1 cannabinoid receptors on GABAergic nerve terminals activates the dopaminergic reward system by increasing dopamine release in the rat nucleus accumbens.	2009 Jun	19428788
Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine.	2009 Mar 10	19284549
Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands.	2009 Oct 23	19723626
Characterization of anandamide-stimulated cannabinoid receptor signaling in human ULTR myometrial smooth muscle cells.	2009 Sep	19477951
Evidences of cannabinoids-induced modulation of paroxysmal events in an experimental model of partial epilepsy in the rat.	2009 Sep 22	19595742
Endocannabinoid regulation of spinal nociceptive processing in a model of neuropathic pain.	2010 Apr	20384778
The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats.	2010 Dec 2	20888328
Retrograde release of endocannabinoids inhibits presynaptic GABA release to second-order baroreceptive neurons in NTS.	2010 Dec 8	20580326
Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids.	2010 Jun	20590570
Evidence for both inverse agonism at the cannabinoid CB1 receptor and the lack of an endogenous cannabinoid tone in the rat and guinea-pig isolated ileum myenteric plexus-longitudinal muscle preparation.	2010 Jun	20590566
GPR55 ligands promote receptor coupling to multiple signalling pathways.	2010 Jun	20136841
Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a peripherally restricted cannabinoid CB1/CB2 receptor agonist, inhibits gastrointestinal motility but has no effect on experimental colitis in mice.	2010 Sep 1	20571060
Interactions between endocannabinoid and serotonergic systems in mood disorders caused by nicotine withdrawal.	2011 Apr	21324836
Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.	2012 Apr	22198381
Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death.	2014 Jan 1	24211273
The psychoactive compound of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC) inhibits the human trophoblast cell turnover.	2015 Aug 6	26070387
The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats.	2015 Jan	25447325

Patents

Sample Use Guides

In Vivo Use Guide

Rats: chronic treatment with AM-251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol.

Route of Administration: Intraperitoneal

In Vitro Use Guide

The application of AM-251 (10 uM) activated a robust Ca2+ accumulation in a subset (≈35–40%) of TG neurons. The AM-251-evoked Ca2+ influxes into murine trigeminal ganglia (TG) sensory neurons were concentration-dependent. The EC50 for AM-251 was 7.37 uM. A wide range of concentrations (0.1–50 uM) of AM-251 is able to generate currents in TG sensory neurons. The activation threshold for IAM-251 was 0.1 uM.

Name

Type

Language

AM-251

Common Name

English

1-(2,4-DICHLOROPHENYL)-5-(4-IODOPHENYL)-4-METHYL-N-PIPERIDIN-1-YLPYRAZOLE-3-CARBOXAMIDE

Systematic Name

English

AM251

Common Name

English

1-(2,4-DICHLOROPHENYL)-5-(4-IODOPHENYL)-4-METHYL-N-(1-PIPERIDYL)PYRAZOLE-3-CARBOXAMIDE

Systematic Name

English

Code System Code Type Description

WIKIPEDIA

AM251