partial and inverse agonists

full agonist vs partial agonist vs inverse agonist

• full agonist = produces complete activation of a receptor at high drug concentrations

• partial agonist = less than 100% activation EVEN at very high concentrations

• inverse agonists = produce a response below the baseline response measured in the absence of drug

partial agonists

• partial agonist = molecules that activate receptors but are unable to elicit the max response of the receptor system even when all of the receptors are occupied (bound) by the agonist

• b/c partial and full agonists bind to the same receptor site → a partial agonist can reduce the response produced by a full agonist → sometimes called “partial antagonists” or “mixed agonist-antagonists”

• partial agonists can be used therapeutically to buffer a response by inhibiting excessive receptor stimulation WITHOUT totally abolishing receptor stimulation

partial agonist and derivatives of trimethylammonium

• derivatives of trimethylammonium stimulate muscarinic acetylcholine (ACh) receptors to cause muscle contraction in gut

  • ligand = acetylcholine (not shown)

  • full agonists = butyl and hexyl

  • partial agonists = heptyl and octyl

partial agonists vs full agonists

• partial agonists can be more or less potent than full agonists

• full agonist = morphine

  • ED50 = 1 mg/kg

• partial agonist = buprenorphine

  • ED 50 = 0.3 mg/kg

  • but does NOT receive same max response

how do partial agonists work?

• hypothesis 1 = stabilize DR form so there is a mixture of DR (inactive) and DR* (active forms)

• hypothesis 2 = receptors may have multiple DR* conformations; each with a different intrinsic activity

• hypothesis 3 = receptor may require a ‘priming’ change BEFORE activation → partial agonist may be less efficient at inducing primed conformation

partial agonist/antagonist

• partial agonists can also act as partial antagonists of full agonists

• as the # of receptors occupied by the partial agonist increases, the # of receptors that can be bound by full agonist decreases

  • decrease in Emax

• high levels of agonist may activate all receptors and produce unwanted overstimulation

• presence of partial agonist displaces some agonist → results in diminished receptor response

• at high concentrations of partial agonist, the agonist is completely displaced and receptor activity is determined by the intrinsic activity of the partial agonist

partial agonists as drugs

• aripiprazole (atypical antipsychotic) = partial agonist for some dopamine receptors

  • overactive dopamine pathways are inhibited by aripiprazole and underactive pathways are stimulated → leads to improved schizophrenia symptoms with a relatively low risk of adverse effects

noncompetitive antagonist vs partial agonist curves

inverse agonists

• inverse agonist = molecule that binds the same binding site on a receptor as an agonist and reverses the intrinsic constitutive activity of the receptor

how do inverse agonists work?

• hypothesis 1 = inverse agonist may keep receptor in bound, inactive complex that prevents baseline R* activity

• R* = inherent activity of R* WITHOUT drug or ligand binding

inverse agonist targets

• receptors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine, bradykinin, and adenosine receptors

  • in systems that are NOT constitutively active or in the presence of a full agonist, inverse agonists will behave like competitive antagonists

summary

• full agonists stabilize DR*

• partial agonists stabilize DR AND DR* (or alternate forms of DR* or primed forms of DR)

• inverse agonists stabilize DR

• competitive antagonists stabilize R by preventing full, partial and inverse agonists from binding to receptor

efficacy review

• full agonists: efficacy = 1

• partial agonists: 0<efficacy<1

• inverse agonists: efficacy<0

• competitive antagonists: efficacy = 0