Partial agonists, full agonists, antagonists: dilemmas of definition

Area of Science:

• Pharmacology
• Molecular Biology
• Biochemistry

Background:

• Characterizing receptors is challenging without selective antagonists, relying heavily on agonists.
• Debate exists regarding the classification of drugs acting on G protein-coupled receptors (GPCRs) as agonists, partial agonists, or antagonists.
• Observed variations in drug intrinsic activity across different preparations complicate receptor pharmacology studies.

Purpose of the Study:

• To review recent data explaining the variability in drug intrinsic activity.
• To address the debate surrounding agonist, partial agonist, and antagonist classifications for GPCR-acting drugs.
• To clarify the influence of receptor reserve and effector coupling on observed drug intrinsic activities.

Main Methods:

• Review of recent pharmacological and biochemical data.
• Analysis of classical receptor theory principles.
• Examination of drug interactions with G protein-coupled receptors (GPCRs).

Main Results:

• Variations in intrinsic activity can be explained by receptor reserve, not solely receptor subtypes or effector coupling.
• Classical receptor theory predicts a range of intrinsic activities for a drug at a given receptor type.
• Different effector systems coupled to the same receptor can lead to varying intrinsic activity observations for a single drug.

Conclusions:

• Drug intrinsic activity at GPCRs is influenced by receptor reserve and the specific effector systems involved.
• Revisiting classical receptor theory provides a framework for understanding these variations.
• This understanding is crucial for accurate receptor characterization and drug classification.