SAR studies of Capsazepinoid Bronchodilators The B-ring and the C-region
(2006)- Abstract
- Capsazepine and similar compounds, capsazepinoids, were shown to be general inhibitors of agonist (leukotriene D4, histamine, acetylcholine, prostaglandin D2) evoked constriction of human small airway preparations. The mechanism of action remains to be elucidated, but established bronchodilator principles, e.g. beta2-adrenoceptor agonism, as well as TRPV1 antagonism were shown to be less likely. From a systematic variation of the structure of capsazepine, divided into four regions, i.e. the fused catechol (A-ring), the fused 2,3,4,7-tetrahydro-1H-azepine (B-ring), the thiourea (coupling) and the 2-(4-chlorophenyl)ethyl (C-region), SAR:s were established. From this study... (More)
- Capsazepine and similar compounds, capsazepinoids, were shown to be general inhibitors of agonist (leukotriene D4, histamine, acetylcholine, prostaglandin D2) evoked constriction of human small airway preparations. The mechanism of action remains to be elucidated, but established bronchodilator principles, e.g. beta2-adrenoceptor agonism, as well as TRPV1 antagonism were shown to be less likely. From a systematic variation of the structure of capsazepine, divided into four regions, i.e. the fused catechol (A-ring), the fused 2,3,4,7-tetrahydro-1H-azepine (B-ring), the thiourea (coupling) and the 2-(4-chlorophenyl)ethyl (C-region), SAR:s were established. From this study 5,8-dichloro-N-[2-(4-chlorophenyl)ethyl]-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide, with a nearly tenfold higher potency compared to capsazepine, emerged. This compound was shown to be similarly potent, but more efficient than established bronchodilators, e.g. salbutamol and formoterol, in dilating human small airway preparations.
SAR findings concerning the B-ring and the C-region of capsazepine, revealed that a conformational constrain, i.e. a fused B-ring, is important to the activity. This ring should preferably be part of a 5,8-dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol and should not be substituted. The C-region should include an aromatic moiety, without bulky substituents, and be linked to the thiourea with a short linker, e.g. methylene or ethylene. In addition the linker could be a ring fused with the benzene ring. The hydrophilicity of capsazepinoids could be increased, without loss of the activity, if the benzene ring in the C-region is replaced with pyridine. Conformational analysis supported the SAR:s suggested.
The attempts to replace the in vivo metabolically labile hydroxyl groups of the catechol moiety with other functional groups all resulted in loss of activity. (Less) - Abstract (Swedish)
- Popular Abstract in Swedish
Astma och rökarsjuka, eller mer korrekt kronisk obstruktiv lungsjukdom (KOL), är två vanliga sjukdomar som karakteriseras av att de drabbade tidvis har svårt att andas. Denna andnöd orsakas av att luftvägarna drar ihop sig. Mediciner som motverkar detta och istället vidgar luftvägarna är därför viktiga för patienter som lider av astma eller KOL. Det finns idag flera mediciner som är effektiva för patienter som lider av astma. Tyvärr är inte alltid dessa mediciner lika effektiva för patienter som lider av KOL. Vi har upptäckt att en kemisk substans, capsazepine, som har likheter med det peppriga ämnet i chilipeppar, kan vidga luftvägarna. Exakt hur capsazepine vidgar luftvägarna vet vi inte, men... (More) - Popular Abstract in Swedish
Astma och rökarsjuka, eller mer korrekt kronisk obstruktiv lungsjukdom (KOL), är två vanliga sjukdomar som karakteriseras av att de drabbade tidvis har svårt att andas. Denna andnöd orsakas av att luftvägarna drar ihop sig. Mediciner som motverkar detta och istället vidgar luftvägarna är därför viktiga för patienter som lider av astma eller KOL. Det finns idag flera mediciner som är effektiva för patienter som lider av astma. Tyvärr är inte alltid dessa mediciner lika effektiva för patienter som lider av KOL. Vi har upptäckt att en kemisk substans, capsazepine, som har likheter med det peppriga ämnet i chilipeppar, kan vidga luftvägarna. Exakt hur capsazepine vidgar luftvägarna vet vi inte, men det förefaller vara på ett tidigare okänt sätt. Eftersom vi inte vet om våra substanser är giftiga kan vi ännu inte ge dem till människor. Istället har vi gjort försök med bitar av lungor som opererats bort ifrån patienter drabbade av lungcancer. Capsazepine är inte särskilt effektivt och man måste ge ganska mycket av substansen för att få någon effekt. Därför har vi undersökt om man kan modifiera det och på så vis göra det mer effektivt. Vi har också försökt ta reda på vilka delar av capsazepine som är viktiga för att det ska ha effekt. Detta arbete har lett fram till en substans som, trots att man ger 10 gånger mindre av den än av capsazepine, har samma effekt som capsazepine. Vi har också undersökt om man kan modifiera capsazepine så att det blir mer vattenlösligt. Vår förhoppning är att de substanser vi tagit fram och den kunskap vi fått om dem ska leda till att man kan utveckla mediciner som inte bara hjälper astmatiker utan även personer som är drabbade av KOL. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/546177
- author
- Berglund, Magnus LU
- supervisor
-
- Olov Sterner LU
- opponent
-
- Associate Professor Grøtli, Morten, Department of Chemistry, Medicinal Chemistry, Göteborg University
- organization
- publishing date
- 2006
- type
- Thesis
- publication status
- published
- subject
- keywords
- Organisk kemi, Organic chemistry, bronchodilator, Capsazepine, structure activity relationship
- pages
- 192 pages
- publisher
- Lund University
- defense location
- Room K:B, Center for Chemistry and Chemical Engineering, Getingevägen 60, Lund Institute of Technology
- defense date
- 2006-02-17 09:30:00
- ISBN
- 91-628-6725-3
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
- id
- 42aa6c80-2440-42a3-bc96-9027d68154a6 (old id 546177)
- date added to LUP
- 2016-04-04 11:10:49
- date last changed
- 2018-11-21 21:03:08
@phdthesis{42aa6c80-2440-42a3-bc96-9027d68154a6,
abstract = {{Capsazepine and similar compounds, capsazepinoids, were shown to be general inhibitors of agonist (leukotriene D4, histamine, acetylcholine, prostaglandin D2) evoked constriction of human small airway preparations. The mechanism of action remains to be elucidated, but established bronchodilator principles, e.g. beta2-adrenoceptor agonism, as well as TRPV1 antagonism were shown to be less likely. From a systematic variation of the structure of capsazepine, divided into four regions, i.e. the fused catechol (A-ring), the fused 2,3,4,7-tetrahydro-1H-azepine (B-ring), the thiourea (coupling) and the 2-(4-chlorophenyl)ethyl (C-region), SAR:s were established. From this study 5,8-dichloro-N-[2-(4-chlorophenyl)ethyl]-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide, with a nearly tenfold higher potency compared to capsazepine, emerged. This compound was shown to be similarly potent, but more efficient than established bronchodilators, e.g. salbutamol and formoterol, in dilating human small airway preparations.<br/><br>
<br/><br>
SAR findings concerning the B-ring and the C-region of capsazepine, revealed that a conformational constrain, i.e. a fused B-ring, is important to the activity. This ring should preferably be part of a 5,8-dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol and should not be substituted. The C-region should include an aromatic moiety, without bulky substituents, and be linked to the thiourea with a short linker, e.g. methylene or ethylene. In addition the linker could be a ring fused with the benzene ring. The hydrophilicity of capsazepinoids could be increased, without loss of the activity, if the benzene ring in the C-region is replaced with pyridine. Conformational analysis supported the SAR:s suggested.<br/><br>
<br/><br>
The attempts to replace the in vivo metabolically labile hydroxyl groups of the catechol moiety with other functional groups all resulted in loss of activity.}},
author = {{Berglund, Magnus}},
isbn = {{91-628-6725-3}},
keywords = {{Organisk kemi; Organic chemistry; bronchodilator; Capsazepine; structure activity relationship}},
language = {{eng}},
publisher = {{Lund University}},
school = {{Lund University}},
title = {{SAR studies of Capsazepinoid Bronchodilators The B-ring and the C-region}},
year = {{2006}},
}