| 1. |
- Berglund, Magnus, et al.
(författare)
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SAR studies of capsazepinoid bronchodilators 3: The thiourea part (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region).
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2529-2540
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Tidskriftsartikel (refereegranskat)abstract
- Certain derivatives and analogues of capsazepine are potent in vitro inhibitors of bronchoconstriction in human small airways. During an investigation of the dependency of the potency on the structural features of the capsazepinoids in the thiourea moiety (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region), it was revealed that capsazepinoids with a thiourea or an amide link between the B-ring and the C-region in general have a good bronchorelaxing activity, while urea is a less attractive choice. Further, it was shown that 1,2,3,4-tetrahydroisoquinolines with a 2-(phenyl)ethyl derivative as the C-region are considerably more potent than those with an octyl group, while 2,3,4,5-tetrahydro-1H-2-benzazepines were found to be more insensitive to the nature of the C-region.
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| 2. |
- Berglund, Magnus, et al.
(författare)
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SAR studies of capsazepinoid bronchodilators. Part 2: Chlorination and catechol replacement in the A-ring.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2513-2528
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Tidskriftsartikel (refereegranskat)abstract
- Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlorination of the A-ring as well as the replacement of the catechol with bioisosteric groups. It is revealed that chlorination of the A-ring has a profound effect on activity. Moreover, di-chlorination of the 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline structure results in a 10-fold increase in potency compared to capsazepine.
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| 3. |
- Dalence, Maria
(författare)
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SAR Studies of Capsazepinod Bronchodilators. The A-ring and the Coupling region
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bronchoconstriction is a hallmark in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Current therapies use bronchodilating agents in order to control the exacerbations produced by limited airflow and improve the quality of life of patients suffering from these diseases. Capsazepine, a compound derived from the active principle of hot pepper (Capsicum annuum), capsaicin, was found in this study to relax the constriction induced by several constricting agents in human small airway smooth muscle in vitro. Assays were performed in order to unravel its mechanism of action. Mechanisms such as Beta2-adrenoreceptor agonism, muscarinic receptor antagonism, TRPV1 mediated mechanism and inhibition of voltage operated calcium channels were excluded, suggesting the possibility of a novel mechanism of action. Capsazepine derivatives (capsazepinoids) were synthesized. This thesis discusses the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepine (7-membered B-ring), 2,3,4,5-tetrahydro-1H-3-benzazepine (symmetrical 7-membered B-ring), 1,2,3,4-tetrahydroisoquinoline (6-membered B-ring) and isoindoline (5-membered B-ring) derivatives having different substitution patterns in the aromatic A-ring. Derivatives where the thiourea functionality in the coupling region has been replaced by either amide or urea were synthesized as well. All derivatives synthesized were tested for its in vitro bronchorelaxing activity using human small bronchi (0.5-1.5 mm of diameter). The values of activity obtained were correlated with the structure of the compounds. The analysis was solely based on structural features since the target is not known. In addition, a conformational analysis of derivatives having 5, 6 and 7-membered B-rings was made in order to strengthen the structure-activity relationships found.
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| 4. |
- Dalence, Maria, et al.
(författare)
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SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2499-2512
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Tidskriftsartikel (refereegranskat)abstract
- Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
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| 5. |
- Skogvall, Staffan, et al.
(författare)
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Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95
- 2008
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 21:1, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Current drugs including beta-agonists have limited smooth muscle relaxant effects on human small airways. Yet this is a major site of obstruction in asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: This study explores human small airway relaxant effects of RESPIR 4-95, a novel chemical analogue (capsazepinoid) to capsazepine. Capsazepine was recently shown to relax small airways in a way which was independent of its TRPV(1) antagonism and independent of current bronchodilator drug mechanisms. METHOD: In vitro preparations of human small airways, 0.5-1.5mm in diameter and responding with reproducible contractions to leukotriene D(4) (LTD(4)) for 12h, were used. RESULTS: RESPIR 4-95 reversibly prevented LTD(4)-induced contractions as well as relaxed the established tonic contraction by LTD(4). RESPIR 4-95 exhibited marked improvements over the reference capsazepinoid, capsazepine, by being 10 times more potent, exhibiting twice as long duration of action after wash-out (9h), and inhibiting equally well LTD(4)-, histamine-, prostaglandin D(2) (PGD(2))-, and acetylcholine (ACh)-induced contractions. RESPIR 4-95 was distinguished from l-type calcium channel antagonist nifedipine by its greater efficacy and potency and by exhibiting increased relaxant effect by repeated exposures. Furthermore, RESPIR 4-95 was more efficacious and longer acting than the long-acting beta-agonist formoterol. CONCLUSION: Efficacy, potency, duration of action, and inexhaustibility of its relaxation of human small airways make RESPIR 4-95 an interesting lead compound for further developments aiming at drug treatment of small airway obstruction in asthma and COPD. Further work is warranted to unveil the molecular biology behind its relaxant actions.
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| 6. |
- Skogvall, Staffan, et al.
(författare)
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Effects of capsazepine on human small airway responsiveness unravel a novel class of bronchorelaxants.
- 2007
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 20, s. 273-280
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Tidskriftsartikel (refereegranskat)abstract
- Capsazepine is known as a transient receptor potential channel vanilloid subfamily 1 (TRPV1) antagonist that inhibits bronchoconstriction evoked in animals by TRPV1 agonists. In this study, effects of capsazepine and chemically related analogues, so called capsazepinoids, were examined in vitro on contractile effects in human small airway preparations. Repeated cycles with 1 h of LTD4-free physiological saline solution followed by 30 min exposure to LTD4 (10 nM) demonstrated that the contractile responsiveness of the preparations exhibited little change over time despite repeated challenges (> 12 h). Capsazepine (1-100 mu M) reversibly and concentration-dependently inhibited the contractile response to LTD4 with EC50 similar to 10 mu M and similar to 90% relaxation at 100 mu M. Capsazepine (10 M) was approximately equally effective to attenuate the contractions evoked by several different inflammatory contractile agonists (LTD4, PGD(2), histamine), and it relaxed preparations with established tonic contraction due to LTD4. Higher concentrations of capsazepine were needed to relax ACh-contractions. The effect of capsazepine on LTD4-induced contractions was not significantly reduced by pre-treating the preparations with either of propranotol (10 mu M) + atropine (1 mu M), L-NAME (1 mM), indomethacin (1 mu M), iberiotoxin (0.1 mu M), capsaicin (10 mu M), and nifedipine (10 mu M). Although the mechanism of action of the present capsazepine-induced bronchorelaxation remains unknown it emerged here that they represent a generally effective principle exerting a functional antagonism against contractile mediators but distinct from beta receptor agonists and inhibitors of L-type calcium channels. The inhibitory effect of capsazepine is shared by chemical analogues, but not with other TRPV1 antagonists, suggesting the possibility that capsazepine represents a novel class of bronchorelaxants effective in human small airways. These findings were not predicted by previous observations that have concerned quite limited effects of capsazepine on airway tone in different animal test systems. If potency can be further increased and the results translated to in vivo, compounds representing the capsazepinoid class of bronchorelaxants might become useful in the treatment of patients suffering from asthma and COPD.
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