DT-Web

DB01359 - Penbutolol


Identification
Name Penbutolol
Accession Number DB01359
Type small molecule
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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 291.4284
Groups approved
Monoisotopic Weight 291.219829177
Pharmacology
Indication Penbutolol 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.
Mechanism of action Penbutolol acts on the ?1 adrenergic receptors in both the heart and the kidney. When ?1 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 ?1 adrenergic receptors and decreases heart rate, which lowers blood pressure.
Absorption >90%.
Protein binding 80-98% bound to plasma proteins. Extensively bound to Alpha-1-acid glycoprotein 1.
Biotransformation Metabolized in the liver by hydroxylation and glucuroconjugation forming a glucuronide metabolite and a semi-active 4-hydroxy metabolite.
Route of elimination The metabolites are excreted principally in the urine.
Toxicity Symptoms of overdose include drowsiness, vertigo, headache, and atriventricular block.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Aminophylline Antagonism of action and increased effect of theophylline
Chlorpropamide The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
Clonidine Increased hypertension when clonidine stopped
Digoxin Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Dihydroergotamine Ischemia with risk of gangrene
Disopyramide The beta-blocker, penbutolol, may increase the toxicity of disopyramide.
Epinephrine Hypertension, then bradycardia
Ergotamine Ischemia with risk of gangrene
Fenoterol Antagonism
Formoterol Antagonism
Gliclazide The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
Glyburide The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
Ibuprofen Risk of inhibition of renal prostaglandins
Indomethacin Risk of inhibition of renal prostaglandins
Insulin Glargine The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
Lidocaine Penbutolol increases the volume of distribution of lidocaine in normal subjects. This could result in a requirement for higher loading doses of lidocaine.
Methyldopa Possible hypertensive crisis
Methysergide Ischemia with risk of gangrene
Orciprenaline Antagonism
Oxtriphylline Antagonism of action and increased effect of theophylline
Pipobroman Antagonism
Piroxicam Risk of inhibition of renal prostaglandins
Prazosin Risk of hypotension at the beginning of therapy
Repaglinide The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
Terazosin Increased risk of hypotension. Initiate concomitant therapy cautiously.
Terbutaline Antagonism
Theophylline Antagonism of action and increased effect of theophylline
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Food Interactions Not Available

Targets


Beta-1 adrenergic receptor
Name Beta-1 adrenergic receptor
Gene Name ADRB1
Pharmacological action yes
Actions antagonist,partial agonist
References
  • Venter CP, Joubert PH: Ethnic differences in beta-1-adrenoceptor sensitivity. S Afr Med J. 1982 Nov 27;62(23):849-50. - Pubmed
  • Sanchez C: Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol. 1993 Jun;4(3):269-277. - Pubmed
  • 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
  • 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
DTHybrid score 0.7206
Beta-2 adrenergic receptor
Name Beta-2 adrenergic receptor
Gene Name ADRB2
Pharmacological action yes
Actions antagonist,partial agonist
References
  • 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
  • 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
  • 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
  • Sanchez C: Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol. 1993 Jun;4(3):269-277. - Pubmed
  • 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
  • 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
DTHybrid score 0.7261
5-hydroxytryptamine 1A receptor
Name 5-hydroxytryptamine 1A receptor
Gene Name HTR1A
Pharmacological action yes
Actions antagonist
References
  • 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
  • Hjorth S: (-)-Penbutolol as a blocker of central 5-HT1A receptor-mediated responses. Eur J Pharmacol. 1992 Nov 3;222(1):121-7. - Pubmed
DTHybrid score 0.246

Carriers


Predictions


Id Partner name Gene Name Score
4119 Cytochrome P450 2D6 CYP2D6 0.1896
1517 Beta-3 adrenergic receptor ADRB3 0.1515
4512 Cytochrome P450 3A4 CYP3A4 0.1201
556 Alpha-1A adrenergic receptor ADRA1A 0.1057
1588 Multidrug resistance protein 1 ABCB1 0.1039
885 5-hydroxytryptamine 1B receptor HTR1B 0.0813
318 Alpha-2A adrenergic receptor ADRA2A 0.0743
502 5-hydroxytryptamine 2A receptor HTR2A 0.0688
587 Serum albumin ALB 0.0679
4200 Cytochrome P450 1A2 CYP1A2 0.0676
6016 Cytochrome P450 2C19 CYP2C19 0.0544
632 Alpha-1B adrenergic receptor ADRA1B 0.0541
831 D(2) dopamine receptor DRD2 0.0519
629 Alpha-2B adrenergic receptor ADRA2B 0.0507
378 Alpha-2C adrenergic receptor ADRA2C 0.0486
6144 Solute carrier family 22 member 2 SLC22A2 0.0452
23 D(1A) dopamine receptor DRD1 0.0431
4757 Cytochrome P450 2C9 CYP2C9 0.0429
540 Sodium-dependent noradrenaline transporter SLC6A2 0.041
4118 Cytochrome P450 3A5 CYP3A5 0.04
725 5-hydroxytryptamine 1D receptor HTR1D 0.0381
6145 Solute carrier family 22 member 1 SLC22A1 0.0381
590 5-hydroxytryptamine 2C receptor HTR2C 0.0372
824 Sodium-dependent serotonin transporter SLC6A4 0.0365
789 Alpha-1D adrenergic receptor ADRA1D 0.0346
6107 Cytochrome P450 3A7 CYP3A7 0.0345
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0329
3941 Amine oxidase [flavin-containing] A MAOA 0.0325
3923 Cholinesterase BCHE 0.0325
6024 Cytochrome P450 1A1 CYP1A1 0.0305
638 D(3) dopamine receptor DRD3 0.0297
716 5-hydroxytryptamine 7 receptor HTR7 0.0286
432 D(4) dopamine receptor DRD4 0.0283
492 Histamine H1 receptor HRH1 0.0274
436 5-hydroxytryptamine 2B receptor HTR2B 0.0263
4924 Cytochrome P450 2C8 CYP2C8 0.0255
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0247
2300 Lysozyme E 0.0243
3633 Lysozyme R 0.0243
5597 Lysozyme 17 0.0243
511 5-hydroxytryptamine 1F receptor HTR1F 0.0216
713 Sodium-dependent dopamine transporter SLC6A3 0.0211
3810 Catechol O-methyltransferase COMT 0.0211
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0206
163 D(1B) dopamine receptor DRD5 0.0201
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0199
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0178
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0176
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0174
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0171
1820 Beta-nerve growth factor NGF 0.0166
787 Vitamin K epoxide reductase complex subunit 1 VKORC1 0.0163
6040 6-phosphogluconate dehydrogenase, decarboxylating PGD 0.016
94 5-hydroxytryptamine 4 receptor HTR4 0.0159
6013 Cytochrome P450 2E1 CYP2E1 0.0155
5718 Cytochrome P450 2A6 CYP2A6 0.0152
4146 Phosphatidylinositol 3-kinase regulatory subunit gamma PIK3R3 0.0151
4145 Phosphatidylinositol 3-kinase regulatory subunit beta PIK3R2 0.0151
828 Phenylalanine-4-hydroxylase PAH 0.0149
3109 Phenylalanine-4-hydroxylase phhA 0.0149
1256 5-hydroxytryptamine 6 receptor HTR6 0.0131
1281 Phosphatidylinositol 3-kinase regulatory subunit alpha PIK3R1 0.0125
4292 Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase lpxA 0.0124
6106 Cytochrome P450 2C18 CYP2C18 0.0122
3076 Antigen 85-C fbpC 0.0122
6147 Solute carrier family 22 member 3 SLC22A3 0.0118
777 Tumor necrosis factor TNF 0.0112
844 Epidermal growth factor receptor EGFR 0.0106
465 Calmodulin CALM1 0.0105
6030 Cytochrome P450 2B6 CYP2B6 0.0105
862 Multidrug resistance-associated protein 1 ABCC1 0.0101
118 Organic cation/carnitine transporter 2 SLC22A5 0.0097
528 5-hydroxytryptamine 1E receptor HTR1E 0.0095
6847 Lactase-phlorizin hydrolase LCT 0.0093
3939 Amine oxidase [flavin-containing] B MAOB 0.0093
183 Vascular endothelial growth factor A VEGFA 0.0089
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0086
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0086
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0086
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0083
20 Prostaglandin G/H synthase 1 PTGS1 0.0083
1176 Mitogen-activated protein kinase 1 MAPK1 0.0083
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0079
341 5-hydroxytryptamine 3 receptor HTR3A 0.0078
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0072
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0072
514 Potassium voltage-gated channel subfamily H member 6 KCNH6 0.0072
772 Potassium voltage-gated channel subfamily H member 7 KCNH7 0.0072
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0067
6169 ATP-binding cassette sub-family A member 5 ABCA5 0.0066
124 Histamine H2 receptor HRH2 0.0066
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0065
1374 Natriuretic peptides B NPPB 0.0061
1827 Gap junction alpha-1 protein GJA1 0.0061
1908 Vascular cell adhesion protein 1 VCAM1 0.0061
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0061
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.006
6180 UDP-glucuronosyltransferase 2B4 UGT2B4 0.006
1656 CYP2B protein CYP2B 0.0059
847 Mu-type opioid receptor OPRM1 0.0059
131 Synaptic vesicular amine transporter SLC18A2 0.0058
6432 Transporter snf 0.0057
1360 Sphingomyelin phosphodiesterase SMPD1 0.0056
3876 Aromatic-L-amino-acid decarboxylase DDC 0.0055
1050 Bile salt sulfotransferase SULT2A1 0.0052
1757 Myeloperoxidase MPO 0.0052
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0052
698 B-Raf proto-oncogene serine/threonine-protein kinase BRAF 0.0052
833 Organic cation/carnitine transporter 1 SLC22A4 0.0051
194 NADH dehydrogenase [ubiquinone] 1 subunit C2 NDUFC2 0.005
5787 Angiopoietin-1 receptor TEK 0.0047
1618 High affinity nerve growth factor receptor NTRK1 0.0047
380 Cytochrome P450 17A1 CYP17A1 0.0046
2164 Multidrug resistance-associated protein 4 ABCC4 0.0046
768 FK506-binding protein 1A FKBP1A 0.0043
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0042
2180 3-phosphoinositide-dependent protein kinase 1 PDPK1 0.0041
696 Kappa-type opioid receptor OPRK1 0.004
6151 Monocarboxylate transporter 10 SLC16A10 0.004
734 D1 dopamine receptor-interacting protein calcyon CALY 0.0039
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.0035
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0034
505 Glutamate [NMDA] receptor subunit epsilon-3 GRIN2C 0.0034
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.0033
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0032
3947 Xanthine dehydrogenase/oxidase XDH 0.0032
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0031
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.003
290 Prostaglandin G/H synthase 2 PTGS2 0.0027
776 Bile salt export pump ABCB11 0.0027
4160 Voltage-dependent calcium channel subunit alpha-2/delta-2 CACNA2D2 0.0027
1898 Cytochrome P450 1B1 CYP1B1 0.0026
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.0026
1284 Nuclear receptor subfamily 1 group I member 2 NR1I2 0.0025
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0025
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0024
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0024
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0024
1864 RET proto-oncogene RET 0.0023
233 Potassium channel subfamily K member 2 KCNK2 0.0023
6141 Sodium/bile acid cotransporter SLC10A1 0.0023
1950 Epithelial discoidin domain-containing receptor 1 DDR1 0.0023
6094 BCR/ABL fusion protein isoform X9 BCR/ABL fusion 0.0023
6170 ATP-binding cassette sub-family A member 3 ABCA3 0.0023
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0022
230 ATP-binding cassette transporter sub-family C member 8 ABCC8 0.0021
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0021
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.002
751 Potassium channel subfamily K member 6 KCNK6 0.002
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.002
4114 Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 0.0019
4112 Voltage-dependent L-type calcium channel subunit beta-4 CACNB4 0.0019
731 HIV-1 protease HIV-1 protease 0.0019
738 Monocarboxylate transporter 1 SLC16A1 0.0019
172 Potassium channel subfamily K member 1 KCNK1 0.0019
951 Macrophage colony-stimulating factor 1 receptor CSF1R 0.0019
950 Alpha platelet-derived growth factor receptor PDGFRA 0.0018
238 Peroxisome proliferator-activated receptor gamma PPARG 0.0018
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0018
6017 Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1 0.0018
333 Voltage-dependent L-type calcium channel subunit beta-1 CACNB1 0.0017
228 Beta platelet-derived growth factor receptor PDGFRB 0.0017
158 Sodium channel protein type 1 subunit alpha SCN1A 0.0017
467 Delta-type opioid receptor OPRD1 0.0017
504 Mast/stem cell growth factor receptor KIT 0.0016
1974 Oligopeptide transporter, kidney isoform SLC15A2 0.0016
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0016
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0015
17 Proto-oncogene tyrosine-protein kinase ABL1 ABL1 0.0015
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0015
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0015
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0014
1729 Solute carrier family 22 member 6 SLC22A6 0.0013
164 Histamine H4 receptor HRH4 0.0011
6142 Solute carrier family 22 member 8 SLC22A8 0.001
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