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Identification
Name Lofexidine
Accession Number DB04948
Type small molecule
Groups approved
Description

Lofexidine is an alpha2-adrenergic receptor agonist. It can be used as a short acting anti-hypertensive, but is mostly used to help relieve symptoms of heroin or opiate withdrawal in opiate dependency. It is approved in the United Kingdom, but is still undergoing clinical trials in the United States.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • 2-(1-(2,6-Dichlorophenoxy)ethyl)-4,5-dihydro-1H-imidazole
  • 2-(alpha-(2,6-Dichlorophenoxy)ethyl)2-imidazoline
  • Lofexidina [inn-spanish]
  • lofexidine
  • Lofexidine hydrochloride
  • Lofexidinum [inn-latin]
Brand names
  • BritLofex
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
  • Adrenergic alpha-Agonists
  • Narcotic Antagonists
CAS number 31036-80-3
Weight Average: 259.132
Monoisotopic: 258.032668430
Chemical Formula C11H12Cl2N2O
InChI Key InChIKey=KSMAGQUYOIHWFS-UHFFFAOYSA-N
InChI
InChI=1S/C11H12Cl2N2O/c1-7(11-14-5-6-15-11)16-10-8(12)3-2-4-9(10)13/h2-4,7H,5-6H2,1H3,(H,14,15)
Plain Text
IUPAC Name
2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole
SMILES
CC(OC1=C(Cl)C=CC=C1Cl)C1=NCCN1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Ethers
  • Halobenzenes
  • Anisoles
  • Phenyl Esters
Substructures
  • Imidazolines
  • Carboxylic Acids and Derivatives
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamidines
  • Anisoles
  • Imines
  • Phenyl Esters
Pharmacology
Indication Investigated for use/treatment in addictions and substance abuse.
Pharmacodynamics Lofexidine is an orally active imidazoline adrenergic alpha-2-receptor agonist; and is believed to have a high affinity for 2A receptor subtypes resulting in less anti-hypertensive activity than clonidine, a non-selective alpha-2-receptor agonist. Hypotension may occur in susceptible subjects, accompanied by a decrease in heart rate. Abrupt discontinuation of lofexidine has been, in some cases, associated with a transient increase in blood pressure to higher than pre-treatment levels. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By fooling the brain into believing that catecholamine levels are higher than they really are, lofexidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure. This central action is responsible for the suppression of opiate withdrawal symptoms.
Mechanism of action Lofexidine is an alpha2-adrenergic receptor agonist.
Absorption Lofexidine is extensively absorbed and achieves peak plasma concentration at 3 hours after administration of a single dose. Bioavailability is over 90% following oral administration.
Volume of distribution Not Available
Protein binding 80 to 90%
Metabolism

Lofexidine undergoes extensive metabolism in the liver and excretion is mainly by the kidney.
Route of elimination Not Available
Half life 11 hours
Clearance Not Available
Toxicity Lofexidine was tolerated at high dosage in singe dose toxicity studies in animals, the LD50 being >77 mg/kg. With repeat dosing in mice, rats and dogs symptoms related to the pharmacology of the drug (ataxia, sedation, tremor, unkempt appearance and exhaustion) appeared. Overdosage may cause hypotension, bradycardia and sedation.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Tablet, film coated Oral
Prices Not Available
Patents Not Available
Properties
State solid
Melting point 127 oC
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 1.47e-01 g/l ALOGPS
logP 3.31 ALOGPS
logP 2.66 ChemAxon Molconvert
logS -3.25 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 33.62 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 64.41 ChemAxon Molconvert
polarizability 25.11 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Walsh SL, Strain EC, Bigelow GE: Evaluation of the effects of lofexidine and clonidine on naloxone-precipitated withdrawal in opioid-dependent humans. Addiction. 2003 Apr;98(4):427-39. Pubmed
  2. Manufacturer Website Link
External Links
Resource Link
PubChem Compound 30668 Link_out
PubChem Substance 46508453 Link_out
ChemSpider 28460 Link_out
ChEBI 51368 Link_out
ChEMBL 51368 Link_out
Therapeutic Targets Database DAP000064 Link_out
Drug Product Database 0 Link_out
Wikipedia http://en.wikipedia.org/wiki/Lofexidine Link_out
ATC Codes
  • N07BC04
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Food Interactions Not Available
Targets

1. Alpha-2A adrenergic receptor

Pharmacological action: yes
Actions: agonist

Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol

Organism class: human
UniProt ID: P08913 Link_out
Gene: ADRA2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Jin Y, Verstappen A, Elko E, Cammarata P, Yorio T: Effects of lofexidine, an alpha 2-adrenoreceptor agonist, on ocular blood flow and ion transport of rabbit iris-ciliary body. J Ocul Pharmacol. 1992 Spring;8(1):23-33. Pubmed
  2. Strang J, Bearn J, Gossop M: Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Am J Addict. 1999 Fall;8(4):337-48. Pubmed
  3. Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J: Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology. 2000 Aug;23(2):138-50. Pubmed
Comments
Drug created on October 21, 2007 16:23 / Updated on April 19, 2011 15:14

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