Objective: To analyze the effect of two different beta3-adrenoceptor agonists, ZD7114 and ZD2079 on 24h energy expenditure (EE) and substrate oxidations in obese weight-stable subjects.
Design: Measurements of 24 h EE in a respiration chamber, before and after 14 days of treatment with one of the two beta3-agonists or placebo during weight maintenance.
Subjects: ZD7114 study: 7 male and 15 female subjects, body mass index (BMI) 28-39 kg/m2, age 27-64 y; ZD2079 study: 10 male and 7 female subjects, BMI 27-39 kg/m2, age 31-60 y.
Measurements: EE was measured by indirect calorimetry, spontaneous physical activity (SPA) assessed by microwave radar, and 24 h heart rate was registered by telemetry. Serum potassium was measured to test for possible beta2-adrenoceptor activity.
Results: No effects of ZD7114 were found on tested parameters whereas there was a trend for a stimulatory effect of ZD2079 on 24h EE (day 14-pretreatment; ZD2079 vs placebo: 0.4 +/- 1.1 vs -2.0 +/- 0.4%, P = 0.06) and on SPA (day 14-pretreatment; ZD2079 vs placebo: 3.4 +/- 4.5 vs -7.7 +/- 2.7%, P = 0.05). However, average 24 h heart rate decreased from 77.5 +/- 3.2 to 73.8 +/- 2.6 min(-1) from pre-treatment to day 14 with placebo but remained the same with ZD2079 (P = 0.03). The latter suggests some beta1-adrenoceptor activity of the compound.
Conclusion: The lack of thermogenic response with ZD7114 and the very small and questionable response with ZD2079 probably demonstrate a lack of consistency between species in the responsiveness to beta3-stimulation or a diversity in structure of the beta3 receptor since both compounds have proven markedly selective thermogenic beta3-properties in rodents.