AGONIST-ANTAGONIST (MIXED)

A mixed agonist-antagonist is a drug or receptor ligand that possesses pharmacological properties similar to both Agonists and Antagonists for certain Receptor sites. Well-known mixed agonist-antagonists are drugs that interact with Opioid (morphine-like) receptors. Pentazocine, nalbuphine, butorphanol, and Buprenorphine are all mixed agonist-antagonists for opioid receptors. These drugs bind to the μ (mu) opioid receptor to compete with other substances (e.g., Morphine) for this binding site; they either block the binding of other drugs to the μ receptor (i.e., competitive antagonists) or produce a much smaller effect than that of "full" agonists (i.e., they are only partial agonists). Therefore, these drugs block the effects of high doses of morphine-like drugs at μ opioid receptors, while producing partial agonist effects at κ (kappa) and/or δ (delta) opioid receptors. Some of the mixed opioid agonist-antagonists likely produce analgesia (pain reduction) and other morphine-like effects in the Central Nervous System by binding as agonists to κ opioid receptors.

In many cases, however, there is an upper limit (ceiling) to some of the central nervous system effects of these drugs (e.g., respiratory depression). Furthermore, in people physically addicted to morphine-like drugs, the administration of a mixed opioid agonist-antagonist can produce an abstinence (Withdrawal) syndrome by blocking the μ opioid receptor and preventing the effects of any μ agonists (i.e., morphine) that may be in the body. Pretreatment with these drugs can also reduce or prevent the euphoria (high) associated with subsequent morphine use, since the μ opioid receptors are competitively antagonized. Therefore, the mixed opioid agonist-antagonists are believed to have less Abuse Liability than full or partial opioid receptor agonists.

As more and more subtypes of receptors are discovered in other Neurotransmitter systems (there are now more than five serotonin receptor subtypes and five dopamine receptor subtypes), it is quite likely that mixed agonist-antagonist drugs will be identified that act on these receptors as well.

BIBLIOGRAPHY

Gilman, A. G., et al. (Eds.). (1990). Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Nick E. Goeders