Inverse agonist

Dose response curves of a full agonist, partial agonist, neutral antagonist, and inverse agonist

In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either.[1] Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists.[2]

A prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic or basal) level activity in the absence of any ligand. An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level.

The efficacy of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% (i.e., negative) efficacy.

Examples

An example of a receptor that possesses basal activity and for which inverse agonists have been identified is the GABAA receptor. Agonists for the GABAA receptor (such as benzodiazepines) create a sedative effect, whereas inverse agonists have anxiogenic effects (for example, Ro15-4513) or even convulsive effects (certain beta-carbolines).[3][4]

Two known endogenous inverse agonists are the Agouti-related peptide (AgRP) and its associated peptide Agouti signalling peptide (ASIP). Both appear naturally in humans, and each binds melanocortin receptors 4 and 1 (Mc4R and Mc1R), respectively, with nanomolar affinities.[5]

The opioid antagonists naloxone and naltrexone are also partial inverse agonists at mu opioid receptors.

See also

References

  1. ↑ Kenakin T (April 2004). "Principles: receptor theory in pharmacology". Trends in Pharmacological Sciences. 25 (4): 186–92. PMID 15063082. doi:10.1016/j.tips.2004.02.012.
  2. ↑ Inverse agonists - What do they mean for psychiatry? doi: 10.1016/j.euroneuro.2016.11.013
  3. ↑ Mehta AK, Ticku MK (August 1988). "Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels". The Journal of Pharmacology and Experimental Therapeutics. 246 (2): 558–64. PMID 2457076.
  4. ↑ Sieghart W (January 1994). "Pharmacology of benzodiazepine receptors: an update". Journal of Psychiatry & Neuroscience. 19 (1): 24–9. PMC 1188559 Freely accessible. PMID 8148363.
  5. ↑ Ollmann MM, Lamoreux ML, Wilson BD, Barsh GS (February 1998). "Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo". Genes & Development. 12 (3): 316–30. PMC 316484 Freely accessible. PMID 9450927. doi:10.1101/gad.12.3.316.

Further reading

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