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Identification
NamePenbutolol
Accession NumberDB01359
TypeSmall Molecule
GroupsApproved, Investigational
Description

Penbutolol is a drug in the beta-blocker class used to treat hypertension. Penbutolol binds both beta-1 and beta-2 adrenergic receptors, rendering it a non-selective beta-blocker. Penbutolol can act as a partial agonist at beta adrenergic receptors, since it is a sympathomimetric drug. Penbutolol also demonstrates high binding affinity to the 5-hydroxytryptamine receptor 1A with antagonistic effects. This binding characteristic of penbutolol is being investigated for its implications in Antidepressant Therapy. Penbutolol is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity.

Structure
Thumb
Synonyms
(2S)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol
1-(tert-Butylamino)-3-(o-cyclopentylphenoxy)propan-2-ol
2-Propanol, 1-(2-cyclopentylphenoxy)-3-((1,1-dimethylethyl)amino)-, (S)-
HOE 893
HOE 893D
Levatol
Penbutolol
Penbutololum
External Identifiers Not Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
BetapressinHoechst Ltd.
LevatololNot Available
LobetaSanofi-Aventis
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Penbutolol sulfate
Thumb
  • InChI Key: KTXVDQNRHZQBOR-RSAXXLAASA-N
  • Monoisotopic Mass: 389.187208419
  • Average Mass: 389.507
DBSALT000137
Categories
UNII78W62V43DY
CAS number38363-40-5
WeightAverage: 291.4284
Monoisotopic: 291.219829177
Chemical FormulaC18H29NO2
InChI KeyInChIKey=KQXKVJAGOJTNJS-HNNXBMFYSA-N
InChI
InChI=1S/C18H29NO2/c1-18(2,3)19-12-15(20)13-21-17-11-7-6-10-16(17)14-8-4-5-9-14/h6-7,10-11,14-15,19-20H,4-5,8-9,12-13H2,1-3H3/t15-/m0/s1
IUPAC Name
(2S)-1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-ol
SMILES
CC(C)(C)NC[[email protected]](O)COC1=CC=CC=C1C1CCCC1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenol ethers
Direct ParentPhenol ethers
Alternative Parents
Substituents
  • Phenol ether
  • Alkyl aryl ether
  • Secondary alcohol
  • 1,2-aminoalcohol
  • Secondary amine
  • Ether
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationPenbutolol is indicated in the treatment of mild to moderate arterial hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.Penbutolol is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity.
PharmacodynamicsPenbutolol is a ß-1, ß-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol.
Mechanism of actionPenbutolol acts on the β1 adrenergic receptors in both the heart and the kidney. When β1 receptors are activated by catecholamines, they stimulate a coupled G protein that leads to the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The increase in cAMP leads to activation of protein kinase A (PKA), which alters the movement of calcium ions in heart muscle and increases the heart rate. Penbutolol blocks the catecholamine activation of β1 adrenergic receptors and decreases heart rate, which lowers blood pressure.
Related Articles
Absorption>90%.
Volume of distributionNot Available
Protein binding80-98% bound to plasma proteins. Extensively bound to Alpha-1-acid glycoprotein 1.
Metabolism

Metabolized in the liver by hydroxylation and glucuroconjugation forming a glucuronide metabolite and a semi-active 4-hydroxy metabolite.

Route of eliminationThe metabolites are excreted principally in the urine.
Half lifePlasma= approximately 5h Conjugated= approximately 20h in healthy persons, 25h in healthy elderly persons, and 100h in patients on renal dialysis.
Clearance

Approximately 90% of the metabolites are excreted in the urine.

ToxicitySymptoms of overdose include drowsiness, vertigo, headache, and atriventricular block.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Penbutolol Action PathwayDrug actionSMP00305
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9935
Blood Brain Barrier-0.747
Caco-2 permeable+0.5961
P-glycoprotein substrateSubstrate0.6827
P-glycoprotein inhibitor INon-inhibitor0.7493
P-glycoprotein inhibitor IINon-inhibitor0.7789
Renal organic cation transporterNon-inhibitor0.8696
CYP450 2C9 substrateNon-substrate0.7898
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateNon-substrate0.6339
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.8899
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7132
Ames testNon AMES toxic0.8317
CarcinogenicityNon-carcinogens0.8643
BiodegradationNot ready biodegradable0.9927
Rat acute toxicity2.3931 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9436
hERG inhibition (predictor II)Non-inhibitor0.5704
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
  • Schwarz Pharma Inc.
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Levatol 20 mg tablet2.87USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
boiling point438.2http://www.chemnet.com/cas/fr/38363-40-5/Penbutolol.html
logP4.15HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.0212 mg/mLALOGPS
logP3.84ALOGPS
logP3.55ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)14.09ChemAxon
pKa (Strongest Basic)9.76ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area41.49 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity86.6 m3·mol-1ChemAxon
Polarizability34.58 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (49.2 KB)
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Maurer HH, Tenberken O, Kratzsch C, Weber AA, Peters FT: Screening for library-assisted identification and fully validated quantification of 22 beta-blockers in blood plasma by liquid chromatography-mass spectrometry with atmospheric pressure chemical ionization. J Chromatogr A. 2004 Nov 26;1058(1-2):169-81. [PubMed:15595665 ]
  2. Aguirre C, Rodriguez-Sasiain JM, Calvo R: Decrease in penbutolol protein binding as a consequence of treatment with some alkylating agents. Cancer Chemother Pharmacol. 1994;34(1):86-8. [PubMed:8174208 ]
  3. Hjorth S: (-)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses. Eur J Pharmacol. 1992 Nov 3;222(1):121-7. [PubMed:1468487 ]
  4. Pepe S, Scalici G, D'Angelo A, Curiale B, Corrao S, Agnello C: [Validity of the use of penbutolol in essential arterial hypertension]. Minerva Med. 1990 Jun;81(6):471-3. [PubMed:2359502 ]
  5. Frishman WH, Covey S: Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism. J Clin Pharmacol. 1990 May;30(5):412-21. [PubMed:2189902 ]
  6. Martinez Jorda R, Aguirre C, Calvo R, Rodriguez-Sasiain JM, Erill S: Decrease in penbutolol central response as a cause of changes in its serum protein binding. J Pharm Pharmacol. 1990 Mar;42(3):164-6. [PubMed:1974610 ]
External Links
ATC CodesC07AA23C07CA23
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (56.3 KB)
MSDSDownload (568 KB)
Interactions
Drug Interactions
Drug
AcepromazineAcepromazine may increase the hypotensive activities of Penbutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Penbutolol is combined with Acetylcholine.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Penbutolol.
AlfuzosinPenbutolol may increase the orthostatic hypotensive activities of Alfuzosin.
AmifostinePenbutolol may increase the hypotensive activities of Amifostine.
AmiodaroneAmiodarone may increase the bradycardic activities of Penbutolol.
BretyliumBretylium may increase the bradycardic activities of Penbutolol.
BrimonidineBrimonidine may increase the antihypertensive activities of Penbutolol.
BupivacaineThe serum concentration of Bupivacaine can be increased when it is combined with Penbutolol.
ButabarbitalThe serum concentration of Penbutolol can be decreased when it is combined with Butabarbital.
ButethalThe serum concentration of Penbutolol can be decreased when it is combined with Butethal.
CabergolinePenbutolol may increase the vasoconstricting activities of Cabergoline.
CarbacholThe risk or severity of adverse effects can be increased when Penbutolol is combined with Carbachol.
CeritinibPenbutolol may increase the bradycardic activities of Ceritinib.
ChloroquineThe metabolism of Penbutolol can be decreased when combined with Chloroquine.
ChlorpropamidePenbutolol may increase the hypoglycemic activities of Chlorpropamide.
DiazoxideDiazoxide may increase the hypotensive activities of Penbutolol.
DigoxinPenbutolol may increase the bradycardic activities of Digoxin.
DipivefrinDipivefrin may increase the atrioventricular blocking (AV block) activities of Penbutolol.
DipyridamoleDipyridamole may increase the bradycardic activities of Penbutolol.
DisopyramideDisopyramide may increase the bradycardic activities of Penbutolol.
DronedaroneDronedarone may increase the bradycardic activities of Penbutolol.
DuloxetinePenbutolol may increase the orthostatic hypotensive activities of Duloxetine.
EsmololEsmolol may increase the bradycardic activities of Penbutolol.
FingolimodPenbutolol may increase the bradycardic activities of Fingolimod.
FloctafenineThe risk or severity of adverse effects can be increased when Floctafenine is combined with Penbutolol.
HeptabarbitalThe serum concentration of Penbutolol can be decreased when it is combined with Heptabarbital.
HexobarbitalThe serum concentration of Penbutolol can be decreased when it is combined with Hexobarbital.
InfliximabInfliximab may decrease the antihypertensive activities of Penbutolol.
IvabradinePenbutolol may increase the bradycardic activities of Ivabradine.
LacosamidePenbutolol may increase the atrioventricular blocking (AV block) activities of Lacosamide.
LevodopaPenbutolol may increase the orthostatic hypotensive activities of Levodopa.
LidocaineThe serum concentration of Lidocaine can be increased when it is combined with Penbutolol.
MepivacaineThe serum concentration of Mepivacaine can be increased when it is combined with Penbutolol.
MethacholineThe risk or severity of adverse effects can be increased when Penbutolol is combined with Methacholine.
MethohexitalThe serum concentration of Penbutolol can be decreased when it is combined with Methohexital.
MethylphenidateMethylphenidate may decrease the antihypertensive activities of Penbutolol.
MidodrinePenbutolol may increase the bradycardic activities of Midodrine.
MolsidomineMolsidomine may increase the hypotensive activities of Penbutolol.
MoxonidineMoxonidine may increase the hypotensive activities of Penbutolol.
NicorandilNicorandil may increase the hypotensive activities of Penbutolol.
NifedipineNifedipine may increase the hypotensive activities of Penbutolol.
ObinutuzumabPenbutolol may increase the hypotensive activities of Obinutuzumab.
OctreotideOctreotide may increase the bradycardic activities of Penbutolol.
OrciprenalinePenbutolol may decrease the activities of Orciprenaline.
PentobarbitalThe serum concentration of Penbutolol can be decreased when it is combined with Pentobarbital.
PentoxifyllinePentoxifylline may increase the hypotensive activities of Penbutolol.
PhenelzinePhenelzine may increase the orthostatic hypotensive activities of Penbutolol.
PrazosinPenbutolol may increase the orthostatic hypotensive activities of Prazosin.
PrimidoneThe serum concentration of Penbutolol can be decreased when it is combined with Primidone.
PropafenoneThe serum concentration of Penbutolol can be increased when it is combined with Propafenone.
QuinineQuinine may increase the hypotensive activities of Penbutolol.
RegorafenibRegorafenib may increase the bradycardic activities of Penbutolol.
ReserpineReserpine may increase the hypotensive activities of Penbutolol.
RisperidonePenbutolol may increase the hypotensive activities of Risperidone.
RituximabPenbutolol may increase the hypotensive activities of Rituximab.
RivastigmineRivastigmine may increase the bradycardic activities of Penbutolol.
RuxolitinibRuxolitinib may increase the bradycardic activities of Penbutolol.
SecobarbitalThe serum concentration of Penbutolol can be decreased when it is combined with Secobarbital.
SufentanilSufentanil may increase the bradycardic activities of Penbutolol.
TacrineTacrine may increase the bradycardic activities of Penbutolol.
TadalafilTadalafil may increase the antihypertensive activities of Penbutolol.
TheophyllinePenbutolol may decrease the activities of Theophylline.
TofacitinibTofacitinib may increase the bradycardic activities of Penbutolol.
TranylcypromineTranylcypromine may increase the orthostatic hypotensive activities of Penbutolol.
TreprostinilTreprostinil may increase the hypotensive activities of Penbutolol.
ValsartanThe risk or severity of adverse effects can be increased when Valsartan is combined with Penbutolol.
VardenafilVardenafil may increase the antihypertensive activities of Penbutolol.
YohimbineYohimbine may decrease the antihypertensive activities of Penbutolol.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistpartial agonist
General Function:
Receptor signaling protein activity
Specific Function:
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Mediates Ras activation through G(s)-alpha- and cAMP-mediated signaling.
Gene Name:
ADRB1
Uniprot ID:
P08588
Molecular Weight:
51322.1 Da
References
  1. Venter CP, Joubert PH: Ethnic differences in beta-1-adrenoceptor sensitivity. S Afr Med J. 1982 Nov 27;62(23):849-50. [PubMed:6755764 ]
  2. Sanchez C: Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol. 1993 Jun;4(3):269-277. [PubMed:11224195 ]
  3. Doze P, Elsinga PH, Maas B, Van Waarde A, Wegman T, Vaalburg W: Synthesis and evaluation of radiolabeled antagonists for imaging of beta-adrenoceptors in the brain with PET. Neurochem Int. 2002 Feb;40(2):145-55. [PubMed:11738481 ]
  4. Frishman WH, Covey S: Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism. J Clin Pharmacol. 1990 May;30(5):412-21. [PubMed:2189902 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistpartial agonist
General Function:
Protein homodimerization activity
Specific Function:
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.
Gene Name:
ADRB2
Uniprot ID:
P07550
Molecular Weight:
46458.32 Da
References
  1. Kulkarni RD, DaSilva LM, Chabria NL, Chadha DR: Beta-2 adrenoceptor blocking activity of penbutolol and propranolol at very low doses. Clin Pharmacol Ther. 1977 Jun;21(6):685-90. [PubMed:16716 ]
  2. Hjorth S, Sharp T: In vivo microdialysis evidence for central serotonin1A and serotonin1B autoreceptor blocking properties of the beta adrenoceptor antagonist (-)penbutolol. J Pharmacol Exp Ther. 1993 May;265(2):707-12. [PubMed:8098761 ]
  3. Hjorth S, Bengtsson HJ, Milano S: Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or beta-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo. Eur J Pharmacol. 1996 Nov 28;316(1):43-7. [PubMed:8982649 ]
  4. Sanchez C: Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol. 1993 Jun;4(3):269-277. [PubMed:11224195 ]
  5. Ijzerman AP, Nagesser A, Garritsen A: The membrane stabilizing activity of beta-adrenoceptor ligands. Quantitative evaluation of the interaction of phenoxypropanolamines with the [3H]batrachotoxinin A 20-alpha-benzoate binding site on voltage-sensitive sodium channels in rat brain. Biochem Pharmacol. 1987 Dec 15;36(24):4239-44. [PubMed:2446632 ]
  6. Frishman WH, Covey S: Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism. J Clin Pharmacol. 1990 May;30(5):412-21. [PubMed:2189902 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G pro...
Gene Name:
HTR1A
Uniprot ID:
P08908
Molecular Weight:
46106.335 Da
References
  1. Rabiner EA, Gunn RN, Castro ME, Sargent PA, Cowen PJ, Koepp MJ, Meyer JH, Bench CJ, Harrison PJ, Pazos A, Sharp T, Grasby PM: beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy. Neuropsychopharmacology. 2000 Sep;23(3):285-93. [PubMed:10942852 ]
  2. Hjorth S: (-)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses. Eur J Pharmacol. 1992 Nov 3;222(1):121-7. [PubMed:1468487 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
antagonist
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of ...
Gene Name:
HTR1B
Uniprot ID:
P28222
Molecular Weight:
43567.535 Da
References
  1. Hjorth S, Sharp T: In vivo microdialysis evidence for central serotonin1A and serotonin1B autoreceptor blocking properties of the beta adrenoceptor antagonist (-)penbutolol. J Pharmacol Exp Ther. 1993 May;265(2):707-12. [PubMed:8098761 ]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
other/unknown
General Function:
Not Available
Specific Function:
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Gene Name:
ORM1
Uniprot ID:
P02763
Molecular Weight:
23511.38 Da
References
  1. Martinez Jorda R, Aguirre C, Calvo R, Rodriguez-Sasiain JM, Erill S: Decrease in penbutolol central response as a cause of changes in its serum protein binding. J Pharm Pharmacol. 1990 Mar;42(3):164-6. [PubMed:1974610 ]
  2. Aguirre C, Rodriguez-Sasiain JM, Calvo R: Decrease in penbutolol protein binding as a consequence of treatment with some alkylating agents. Cancer Chemother Pharmacol. 1994;34(1):86-8. [PubMed:8174208 ]
  3. Aguirre C, Calvo R, Rodriguez-Sasiain JM: Unchanged protein binding of penbutolol in renal insufficiency: a possible role of carbamylation. Int J Clin Pharmacol Ther Toxicol. 1993 Jan;31(1):31-4. [PubMed:8444514 ]
  4. Aguirre C, Troconiz IF, Valdivieso A, Jimenez RM, Gonzalez JP, Calvo R, Rodriguez-Sasiain JM: Pharmacokinetics and pharmacodynamics of penbutolol in healthy and cancer subjects: role of altered protein binding. Res Commun Mol Pathol Pharmacol. 1996 Apr;92(1):53-72. [PubMed:8733828 ]
Comments
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Drug created on July 06, 2007 13:52 / Updated on May 01, 2016 15:53