Assessment of the efficacy and side effect profile of morphine and MMP2200, a mixed delta/mu agonist

Abstract

We have previously reported on the chemistry and preclinical pharmacology of a series of glycosylated enkephalin analogs. These compounds exhibit high affinity/efficacy at delta and mu opioid receptors (DOR and MOR). The current studies present a more detailed characterization of the pharmacology of MMP2200, a lead glycopeptide that incorporates the disaccharide lactose into the peptide structure. MMP2200 produced dose‐related antinociception in the mouse 55°C tail‐flick assay following a variety of routes of administration. The compound was also effective at reversing thermal hyperalgesia (CFA model) and tactile allodynia (plantar incision) in rats. At equi‐antinociceptive doses MMP2200 produced significantly less stimulation of locomotor activity compared to morphine in mice. MMP2200 produced dose‐related inhibition of gastrointestinal transit and respiration similar to that produced by morphine. In summary, MMP2200 acts as a mixed delta/mu agonist in vivo. This profile may account in part for the potent antinociceptive effects seen in several different rodent models of pain, as well as the decreased propensity to produce locomotor stimulation compared to morphine. For other measures (inhibition of GI transit and respiratory depression), the compound may exert too strong an effect on the MOR to differentiate it from morphine.