Dual dopamine D2 receptor and beta2-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease: the pre-clinical rationale.
This paper describes the rationale for the development of dual dopamine D2-receptor and beta2-adrenoceptor agonists as potential treatments for the symptoms of chronic obstructive pulmonary disease (COPD). The putative involvement of pulmonary sensory afferent nerves in mediating the key COPD symptoms of breathlessness, cough and excess sputum production is outlined and the hypothesis that activation of D2-receptors on such nerves would modulate their activity is developed. This premise was tested, in a range of animal models, using the first of a novel class of dual dopamine D2-receptor and beta2-adrenoceptor agonists, sibenadet HCl (Viozan, AR-C68397AA). In the course of these studies it was demonstrated that sibenadet, through activation of D2-receptors, inhibited discharge of rapidly adapting receptors and was effective in reducing reflex-induced tachypnoea, mucus production and cough in the dog. Sibenadet, through its activation of beta2-adrenoceptors, was also shown to be an effective bronchodilator with a prolonged duration of action following topical administration to the lungs. These studies also indicated that sibenadet had a wide therapeutic ratio with respect to expected undesirable side-effects such as emesis and cardiovascular disturbances. These results provided a compelling rationale for the initiation of a clinical development programme with sibenadet for the treatment of COPD.
Dougall
I G
IG
Department of Discovery BioScience, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, UK. Iain.Dougall@astrazeneca.com
Young
A
A
Ince
F
F
Jackson
D M
DM
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000818:Animals; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D009475:Neurons, Afferent; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013844:Thiazoles / Q000627:therapeutic use*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D017448:Receptors, Dopamine D2; D013844:Thiazoles; C116267:sibenadet