Pharmacodynamics Opioid receptor blockade Nalmefene acts as an
inverse agonist of the
μ-opioid receptor (MOR) ( = 0.24 nM) and as a weak
partial agonist (Ki = 0.083 nM;
Emax = 20–30%) of the
κ-opioid receptor (KOR), with similar binding for these two receptors but a several-fold preference for the KOR. In another study however, nalmefene had approximately equal affinity for the MOR and KOR.
Side effects typical of KOR activation such as
hallucinations and
dissociation have also been observed with nalmefene in human studies. It is thought that nalmefene activation of KOR may produce
dysphoria and
anxiety. In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower
affinity for the
δ-opioid receptor (DOR) (Ki = 16 nM), where it behaves as an
antagonist. Nalmefene is structurally related to naltrexone and differs from it by substitution of the
ketone group at the C6 position of naltrexone with a
methylene group (CH2). It binds to the MOR with similar affinity relative to naltrexone, but binds "somewhat more avidly" to the KOR and DOR in comparison. A lower dose of 1 μg/kg intravenously resulted in brain MOR blockade of 52% at 5 minutes, 33% at 2 hours, 47% at 4 hours, and 26% at 8 hours. At 26 hours (1.1 days) post-administration, brain MOR occupancy was 83 to 100%; at 50 hours (2.1 days), it was 48 to 72%; and at 74 hours (3.1 days), it was 12 to 46%. Substantial brain MOR occupancy occurs with nalmefene even when blood levels of nalmefene are very low. The prolonged brain MOR occupancy of nalmefene may be due to slow dissociation of nalmefene from MORs consequent to its high MOR affinity.
Metabolism Nalmefene is extensively metabolized in the liver, mainly by conjugation with
glucuronic acid and also by
N-dealkylation. Less than 5% of the dose is excreted unchanged. The
glucuronide metabolite is entirely inactive, while the
N-dealkylated metabolite has minimal pharmacological activity. ==Chemistry==