Ketanserin

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Ketanserin
Clinical data
Trade namesSufrexal
Other namesR41468; R-41468; R-41,468
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50%[1][2]
Protein binding95.0% (mainly albumin[2]
Elimination half-life10–29 hours[3][1][2]
Identifiers
  • 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione
JSmol)
  • c1ccc2c(c1)c(=O)n(c(=O)[nH]2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F
  • InChI=1S/C22H22FN3O3/c23-17-7-5-15(6-8-17)20(27)16-9-11-25(12-10-16)13-14-26-21(28)18-3-1-2-4-19(18)24-22(26)29/h1-8,16H,9-14H2,(H,24,29) checkY
  • Key:FPCCSQOGAWCVBH-UHFFFAOYSA-N checkY
  (verify)

Ketanserin (

Janssen Pharmaceutica in 1980.[5][6] It is not available in the United States.[1]

Uses

Medical uses

Ketanserin is classified as an

National Institute of Health.[8]

It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).[9]

The reduction in hypertension is not associated with reflex tachycardia.[10]

It has been used in cardiac surgery.[11]

A 2000

progressive systemic sclerosis (an autoimmune disorder). While the frequency of the attacks was unaffected by ketanserin, there was a reduction in the duration of the individual attacks. However, due to the significant adverse effect burden, the authors concluded that ketanserin's utility for this indication is likely unbeneficial.[12]

Ketanserin is a selective 5-HT2A receptor antagonist that was initially developed as an anti-hypertensive medicine. However, now the drug is available as a topical gel formulation for treating wounds, burns, ulcers, and anal fissures. Its action is through the acceleration of epithelialization.

Research uses

With

autoradiography.[13] This radio-labeling has enabled the study of serotonin 5-HT2A receptor distribution in the human brain.[14]

An autoradiography study of the human

femtomol per milligram tissue at around 30 years of age to over 100 above 75 years).[15] The same research team found no significant correlation with age in their homogenate
binding study.

Ketanserin has also been used with

radioactively labeled NNC112 in order to image cortical D1 receptors without contamination by 5-HT2 receptors.[16]

Increasing research into the use of psychedelics as antidepressants has seen ketanserin used to both block the hallucinogenic experience, and to disentangle the specific cognitive effects of 5-HT2A activation.[17]

Pharmacology

Human molecular targets of ketanserin[18][19]
Target Affinity (Ki) Ref(s)
α1A-adrenergic 6.3 nM [19]
α1B-adrenergic 6.3 nM [19]
α1D-adrenergic 16 nM [19]
α2A-adrenergic 372 nM (HT29) [18]
α2B-adrenergic 199 nM [18]
α2C-adrenergic 159 nM (opossum) [18]
5-HT1A 1,044–>10,000 nM [19][18]
5-HT1B 2,515–6,300 nM [19][18]
5-HT1D 32–>10,000 nM [19][20][21]
5-HT1E >10,000 nM [18]
5-HT1F 1.25–>10,000 nM [18]
5-HT2A 0.20–9.8 nM [19][18]
5-HT2B 200–3,236 nM [19][18]
5-HT2C 17–186 nM [19][18]
5-HT3 >10,000 nM (rodent) [18]
5-HT4L 1,000 nM (rat) [18]
5-HT5A 20,000 nM [19][18]
5-HT5B 1,000–1,585 nM (rodent) [18]
5-HT6 2,800 nM [18]
5-HT7 320–1,334 nM [19][18]
D1
 190–464 nM [18]
D2
 >10,000 nM [18]
D3
 ?
D4
 148 nM (canine) [18]
D5
 2,500 nM [19][18]
H1
 1.79 nM [18]
DAT >10,000 nM [18]
VMAT1
 1,600 nM [19]
VMAT2
 500 nM [19]

Pharmacodynamics

Ketanserin is a high-affinity non-selective

H1 receptor.[23] It has also been found to block the vesicular monoamine transporter 2 (VMAT2).[24][25]

Pharmacokinetics

The

elimination half-life of ketanserin is 10 to 29 hours.[3][1]

Synthesis

Thieme Patents:[26][27] Sino:[28] Revised:[29] Analogues[30]

Either 3-(2-Chloroethyl)quinazoline-2,4(1H,3H)-dione [5081-87-8] (1a), or alternatively 2,3-dihydro-[1,3]oxazolo[2,3-b]quinazolin-5-one [52727-44-3] (1b) can be used as starting material. Attachment of the sidechain to 4-(4-Fluorobenzoyl)piperidine [56346-57-7] (2) completes synthesis synthesis of Ketanserin (3).

See also

References

  1. ^
    ISBN 978-1-4377-2070-9
    .
  2. ^
    OCLC 231351327
    .
  3. ^
    OCLC 1076237896
    .
  4. ISBN 978-0-913875-27-8
    .
  5. ISBN 978-0-674-03845-5
    .
  6. ISBN 978-1-56019-100-1
    .
  7. ^ ATC/DDD Index
  8. ^ Ketanserin
  9. PMID 8969033
    .
  10. PMID 2786422
    .
  11. PMID 19058975
    .
  12. PMID 10796396
    .
  13. S2CID 23363050
    .
  14. S2CID 23711420
    .
  15. S2CID 40304220
    .
  16. PMID 20029452
    .
  17. PMID 21956447
    .
  18. ^ a b c d e f g h i j k l m n o p q r s t u v w x NIMH Psychoactive Drug Screening Program
  19. ^ a b c d e f g h i j k l m n o "Ketanserin Ligand page". IUPHAR/BPS Guide to PHARMACOLOGY.
  20. ^
    ISBN 978-0-12-801083-9
    .
  21. ISBN 978-0-08-054111-2
    .
  22. S2CID 205882443
    .
  23. ISBN 978-0-470-34429-3
    .
  24. ISBN 978-0-08-087817-1
    .
  25. PMID 9327887
    .
  26. ^ US 4335127, Vandenberk J, Kennis L, Van der Aa M, Van Heertum A, issued 1982, assigned to Janssen Pharmaceutica, N.V. 
  27. ^ EP 0098499, Signorini R, Verga A, issued 1984, assigned to Ravizza SpA 
  28. ^ CN 106866625, Shiwen R, et al., issued 2017, assigned to Shanghai Ding Ya Pharmaceutical Chemistry Science And Technology Ltd) 
  29. doi:10.1002/jhet.1897
    ..
  30. PMID 1479590
    .