μ-Opioid Antagonist Reduces Food Intake and Body Weight in Mice and Rats
Abstract Number: 1715-P
Authors: JASON BLOXHAM, GILLIAN BOTTOMLEY, JAMES HORSWILL, THOMAS KRULLE, PETER WIDDOWSON
Institutions: Oxford, Great Britain
Results: The opioid system is recognised as a key circuitry for reward related behaviours in both humans and rodents and as such is linked with the hedonic value of food intake (FI). Naltrexone (NAL), a non-selective opioid receptor (OR) antagonist (Ant), has been demonstrated to have effects on FI in both rodents and humans. However, its short half-life and issues with liver toxicity mean that its usage as a single therapeutic agent is limited. We hypothesised that a brain penetrant, small molecule, μ-OR Ant with a good oral PK profile should provide a novel approach to body weight (BW) loss.
We have identified a series of orally active μ-OR Ant, exemplified by PSN-MOP-1 (Ki 0.5±0.05nmol/l (μ-OR), 4.9±0.9nmol/l (δ-OR), 107±7nmol/l (κ-OR)). In lean male Sprague-Dawley rats, PSN-MOP-1 (10mg/kg po) significantly reduced 24h chow FI (FI±SEM; Vehicle (VEH) 65.6±3g/kg; PSN-MOP-1 49.8±2g/kg (24%** reduction compared to VEH); sibutramine (SIB) (5mg/kg po) 32.2±3g/kg (51%***); ***P<0.001, **P<0.01).
In diet-induced obese (DIO) female Wistar rats, PSN-MOP-1 (10mg/kg po, bid) also reduced 24h FI and subsequently BW (Change in BW/FI compared to VEH; PSN-MOP-1 -20.0±2.2g (-4.2%)***/-538±41kJ/kg (-63%)***; SIB (5mg/kg po, qd) -19.5±0.6g (-4.1%)***/-736±38kJ/kg (-87%)***). Whilst SIB treatment over 5 days led to a continued BW loss, PSN-MOP-1 showed no further loss beyond that achieved on day 1. (BW on day 6; VEH 477±2g; PSN-MOP-1 454±5g*** (-5%); SIB 434±2g*** (-9%)).
Evaluation of PSN-MOP-1 (30mg/kg po, qd for 4 weeks) in male DIO mice, resulted in a slow-onset but sustained reduction in BW which continued throughout the study and led to a significant reduction in glucose excursion in a terminal oral glucose tolerance test (Change in BW from VEH; PSN-MOP-1 -4.9±0.6g (-11.7%)***; rimonabant (10mg/kg po) -7.4±0.7g (-17.7%)***).
In summary PSN-MOP-1 has demonstrated the ability of a prototypical μ-OR Ant to acutely reduce FI and BW in both mice and rats. In a 28 day study PSN-MOP-1 delivered a pattern of BW loss in DIO mice which resembles that of NAL in humans. Based on these data a μ-OR Ant such as PSN-MOP-1, which has an improved profile compared to NAL, may deliver significant and continued BW loss in humans.