ABSTRACT
AIMS: Davalintide is a second-generation amylinomimetic peptide possessing enhanced pharmacological properties over rat amylin to reduce food intake in preclinical models. The current experiments in rats describe additional glucoregulatory actions of davalintide consistent with amylin agonism, and explore the duration of action of these effects. METHODS: Subcutaneous (SC) injection of davalintide slowed gastric emptying with equal potency to amylin (ED50's = 2.3 and 4.1 µg/kg). This effect was maintained for 8 h with davalintide, but not amylin. Intraperitoneal injection of davalintide also reduced food intake with a potency similar to amylin (ED50's = 5.0 and 11.3 µg/kg). Consistent with amylin agonism, davalintide (10 µg/kg, SC) suppressed the plasma glucagon response over 90 min following an intravenous arginine bolus in anaesthetized rats. The elimination t(½) of davalintide (200 µg/kg, SC) was 26 min, similar to the t(½) of amylin, suggesting that pharmacokinetic-independent mechanisms contribute to davalintide's enhanced duration of action. Binding kinetic studies using ¹²5I davalintide revealed no appreciable dissociation from the amylin nucleus accumbens receptor after 7 h while ¹²5I rat amylin did dissociate from this receptor (K(off) = 0.013/min). Sustained SC infusion of davalintide (275 µg/kg/day) or amylin (300) decreased plasma glucose after an oral glucose challenge at 2 weeks (by 27 and 31%) and suppressed gastric emptying at 3 weeks (by 29 and 47%), demonstrating durable glucoregulatory actions of both peptides. CONCLUSIONS: These data show glucoregulatory properties of davalintide consistent with amylin agonism and suggest that slowed receptor dissociation plays a role in davalintide's prolonged pharmacodynamic actions.