Original Article

International Journal of Obesity (2010) 34, 385–395; doi:10.1038/ijo.2009.238; published online 24 November 2009

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

C M Mack1, C J Soares1, J K Wilson1, J R Athanacio1, V F Turek1, J L Trevaskis1, J D Roth1, P A Smith1, B Gedulin1, C M Jodka1, B L Roland1, S H Adams1, A Lwin1, J Herich1, K D Laugero1, C Vu1, R Pittner1, J R Paterniti Jr1, M Hanley1, S Ghosh1 and D G Parkes1

1Amylin Pharmaceuticals, San Diego, CA, USA

Correspondence: Dr CM Mack, In Vivo Modeling, Amylin Pharmaceuticals, 9360 Towne Centre Drive, San Diego, CA 92121, USA. E-mail: christine.mack@amylin.com

Received 24 July 2009; Revised 2 September 2009; Accepted 6 September 2009; Published online 24 November 2009.

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Abstract

Objective:

 

The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide.

Research design and methods:

 

The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated.

Results:

 

Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2h).

Conclusion:

 

Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

Keywords:

AC2307, davalintide, amylin, food intake, body weight, area postrema

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