Pharmacodynamics +<unk>  Site Ki (nM) Action Species Ref 0.21–1.50.081 Partial agonist HumanMonkey 2.9–6.10.82 Antagonist HumanMonkey 0.62–2.50.44 Antagonist HumanMonkey 77.4 Partial agonist Human σ1 >100,000 σ2 >10,000 Agonist Human >100,000 Rat >100,000 Rat 33,000 (IC50) Inhibitor Rodent Values are Ki (nM), unless otherwise noted. The smallerthe value, the more strongly the drug binds to the site. Opioid receptor modulator<unk>  has been reported to possess these following pharmacological activities: * μ-Opioid receptor (MOR): Very high affinity partial agonist: at low doses, the MOR-mediated effects of<unk>  are comparable to those of other narcotics, but these effects reach a "ceiling" as the receptor population is saturated. This behavior is responsible for several unique properties:<unk>  greatly reduces the effect of most other MOR agonists, can cause precipitated withdrawal when used in actively opioid dependent persons, and has a lower incidence of respiratory depression and fatal overdose relative to full MOR agonists. * κ-Opioid receptor (KOR): High affinity antagonist—this activity is hypothesized to underlie some of the effects of<unk>  on mood disorders and addiction. * δ-Opioid receptor (DOR): High affinity antagonist * Nociceptin receptor (NOP, ORL-1): Weak affinity, very weak partial agonist In simplified terms,<unk>  can essentially be thought of as a nonselective, mixed agonist–antagonist opioid receptor modulator, acting as an unusually high affinity weak partial agonist of the MOR, a high affinity antagonist of the KOR and DOR, and a relatively low affinity, very weak partial agonist of the ORL-1/NOP. Although<unk>  is a partial agonist of the MOR, human studies have found that it acts like a full agonist with respect to analgesia in opioid-intolerant individuals. Conversely,<unk>  behaves like a partial agonist of the MOR with respect to respiratory depression.<unk>  is also known to bind to with high affinity and antagonize the putative ε-opioid receptor. Full analgesic efficacy of<unk>  requires both exon 11- and exon 1-associated μ-opioid receptor splice variants. The active metabolites of<unk>  are not thought to be clinically important in its CNS effects. In positron emission tomography (PET) imaging studies,<unk>  was found to decrease whole-brain MOR availability due to receptor occupancy by 41% (i.e., 59% availability) at 2 mg, 80% (i.e., 20% availability) at 16 mg, and 84% (i.e., 16% availability) at 32 mg. Other actions Unlike some other opioids and opioid antagonists,<unk>  binds only weakly to and possesses little if any activity at the sigma receptor.<unk>  also blocks voltage-gated sodium channels via the local anesthetic binding site, and this underlies its potent local anesthetic properties. Similarly to various other opioids,<unk>  has also been found to act as an agonist of the toll-like receptor 4, albeit with very low affinity. Pharmacokinetics<unk>  is metabolized by the liver, via CYP3A4 (also CYP2C8 seems to be involved) isozymes of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation). The glucuronidation of<unk>  is primarily carried out by UGT1A1 and UGT2B7, and that of norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into bile. The elimination half-life of<unk>  is 20 to 73 hours (mean 37 hours). Due to the mainly hepatic elimination, no risk of accumulation exists in people with renal impairment. One of the major active metabolites of<unk>  is norbuprenorphine, which, in contrast to<unk>  itself, is a full agonist of the MOR, DOR, and ORL-1, and a partial agonist at the KOR. However, relative to<unk> , norbuprenorphine has extremely little antinociceptive potency (1/50th that of<unk> , but markedly depresses respiration (10-fold more than<unk> . This may be explained by very poor brain penetration of norbuprenorphine due to a high affinity of the compound for P-glycoprotein. In contrast to norbuprenorphine,<unk>  and its glucuronide metabolites are negligibly transported by P-glycoprotein. The glucuronides of<unk>  and norbuprenorphine are also biologically active, and represent major active metabolites of<unk> .<unk> -3-glucuronide has affinity for the MOR (Ki = 4.9 pM), DOR (Ki = 270 nM) and ORL-1 (Ki = 36 μM), and no affinity for the KOR. It has a small antinociceptive effect and no effect on respiration. Norbuprenorphine-3-glucuronide has no affinity for the MOR or DOR, but does bind to the KOR (Ki = 300 nM) and ORL-1 (Ki = 18 μM). It has a sedative effect but no effect on respiration.
Buprenorphine
Methadone
Isomethadone
Naltrexone
Normethadone
Tapentadol
Morphine
Acetylmethadol