Dual D2-Receptor and β2-Adrenoceptor Agonists for the Treatment of Airway Diseases. 1. Discovery and Biological Evaluation of Some 7-(2-Aminoethyl)- 4-hydroxybenzothiazol-2(3H)-one Analogues

Bonnert, Roger V.; Brown, Richard Harvey; Chapman, David; Cheshire, David R.; Dixon, J. Michael; Ince, Francis; Kinchin, Elizabeth; Lyons, Amanda; Davis, A. M.; Hallam, Catherine; Harper, SJ; Unitt, John; Dougall, Iain G.; Jackson, D.M.; McKechnie, K.; Young, and Alan; Simpson, Wilfred T.

doi:10.1021/jm980421f

Cited by 44 publications

(21 citation statements)

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“…The development of a long-acting, dual D 2 -receptor and b 2 -adrenoceptor agonist as a novel treatment for chronic obstructive pulmonary disease (COPD) has highlighted the importance of specific drugYphospholipid membrane interactions (4,5). The duration of b 2 -adrenoceptor agonism has been found to correlate with the membrane affinity of compounds that possess either protonated or unprotonated secondary amino groups, at pH 7.4 (4); the former compounds are predominantly cationic, whereas the latter are predominantly electronically neutral.…”

Section: Introductionmentioning

confidence: 99%

The Thermodynamics of the Partitioning of Ionizing Molecules Between Aqueous Buffers and Phospholipid Membranes

et al. 2005

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Section: Introductionmentioning

confidence: 99%

The Thermodynamics of the Partitioning of Ionizing Molecules Between Aqueous Buffers and Phospholipid Membranes

et al. 2005

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“…Furthermore, in the therapy of airway diseases, dual dopamine D 2 receptors (D 2 )/␤ 2 -receptor agonists have been shown to have beneficial effects compared with conventional ␤ 2 -receptor agonists alone (4). Functional experiments indicate that this additional effect is mediated through normalizing the pathological increased activity of sensory nerves (17).…”

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confidence: 99%

Dopamine type 2 receptor expression and function in rodent sensory neurons projecting to the airways

Peiser

Trevisani

Groneberg

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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The mechanism by which these agonists induce bronchodilatation is thought to involve airway sensory nerves. In this study, the expression and function of dopamine D 2 receptor were examined in sensory ganglia supplying the airways. Neuronal dopamine D 2 receptor mRNA expression was demonstrated by single-cell RT-PCR following laser-assisted microdissection. The projection of the neurons to the airways was confirmed by retrograde neuronal labeling. In functional studies, dopamine D 2 receptor agonists (AR-C65116AB and ropinirole) inhibited intraneuronal calcium mobilization in rat capsaicin-sensitive primary sensory neurons and capsaicin-induced plasma extravasation in the rat trachea. Our results provide support to the hypothesis that dopamine D 2 receptor activation inhibits neurogenic inflammation and proinflammatory reflex responses. D 2 dopamine receptor; jugular-nodose ganglion; dorsal root ganglion; rat PHARMACOLOGICAL EVIDENCE SUGGESTS that for the treatment of diseases associated with airway hyperreactivity and airway obstruction, such as bronchial asthma or chronic obstructive pulmonary disease, administration of inhaled dopamine induces bronchodilatation (5, 23) in a dose-related manner (21). Furthermore, in the therapy of airway diseases, dual dopamine D 2 receptors (D 2 )/␤ 2 -receptor agonists have been shown to have beneficial effects compared with conventional ␤ 2 -receptor agonists alone (4). Functional experiments indicate that this additional effect is mediated through normalizing the pathological increased activity of sensory nerves (17).For a better understanding of these clinical observations, more knowledge is needed about the dopamine system in the respiratory tract, especially concerning sensory nerves projecting to the airways. Dopamine has been demonstrated to be localized in some peripheral tissues, also in several nonneuronal cell types (8). There is a 4.4-fold increase in dopamine content compared with the local noradrenalin concentration (1). This excess of dopamine suggests that it acts in a role other than a noradrenaline precursor (20). Various studies suggest that dopamine is released from nerve endings in the periphery and interacts with specific receptors. D 2 , which are divided into two different isoforms derived from alternative RNA splicing (13,25), are present on many neurons in the periphery (24), and their activation can modulate neuronal activity (26). So far, expression of D 2 mRNA has been only reported in rat sensory ganglia (33).However, to our knowledge, no information is available on the expression of dopamine receptors in sensory neurons projecting into the respiratory system, thus the aim of this study is to determine expression and function of dopamine receptors, with particular respect to D 2 . MATERIALS AND METHODSAnimals. For the experiments described below, male SpragueDawley rats (Charles River) were used. All animal studies carried out are conform to Institutional Animal Care and Use Committee guidelines.Retrograde neuronal tracing. Rats were anesthetize...

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“…The structures of a weak β 2 -adrenoceptor agonist (5.65) and a potent D 2 -receptor agonist (5.66) were hybridized to give 5.67. Modification of the side chain gave 5.68, [122] which went into clinical trials for the treatment of the symptoms of COPD.…”

Section: Dual-acting Drugs: Dual-acting Enzyme Inhibitorsmentioning

confidence: 99%

Enzyme Inhibition and Inactivation

Silverman

2014

The Organic Chemistry of Drug Design and Drug Action

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Dual D₂-Receptor and β₂-Adrenoceptor Agonists for the Treatment of Airway Diseases. 1. Discovery and Biological Evaluation of Some 7-(2-Aminoethyl)- 4-hydroxybenzothiazol-2(3H)-one Analogues

Cited by 44 publications

References 17 publications

The Thermodynamics of the Partitioning of Ionizing Molecules Between Aqueous Buffers and Phospholipid Membranes

The Thermodynamics of the Partitioning of Ionizing Molecules Between Aqueous Buffers and Phospholipid Membranes

Dopamine type 2 receptor expression and function in rodent sensory neurons projecting to the airways

Enzyme Inhibition and Inactivation

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