drug receptors

Drugs and Receptors

  • Most drugs act by interacting with proteins, mainly receptors (e.g., neurotransmitters and hormones).

  • Receptor Features:

    • Signal transduction capability modifying cell function.

    • Structure matches the ligand.

  • Forces in Binding (from strongest to weakest):

    1. Covalent bonds

    2. Ionic bonds

    3. Hydrogen bonds

    4. Van der Waals forces

    5. Hydrophobic forces

Agonists and Antagonists: Affinity and Efficacy

  • Definitions:

    • Agonist: Binds and activates receptors (produces response).

    • Antagonist: Binds but does not activate receptors.

  • Response Relationships:

    • Response magnitude correlates with agonist concentration (hyperbolic to sigmoid on log scale).

  • Binding and Efficacy:

    • Proportion of receptors bound influences response size; EC50 denotes the concentration for 50% max response.

Competitive Antagonism

  • Shifts agonist response curve to the right without altering max response; requires higher agonist concentrations.

Structure-Activity Relationships

  • Determines potency of closely related compounds aiding in receptor classification (e.g., nicotinic vs. muscarinic receptors).

Stereochemistry in Drug Action

  • Different stereoisomers can have distinct potencies, affecting receptor interaction.

Radioligand Binding

  • Measures drug-receptor interaction through total and specific binding using radioligand.

  • Specific binding is determined by subtracting non-specific binding.

Quantification of Drug-Receptor Interactions

  • Binding Dynamics:

    • Drug-binding model and rate constants explain receptor occupancy.

  • Saturation Binding: A fraction of receptors binds to drugs; affinity constant (Ka) and dissociation constant (Kd) are derived.

Cooperativity

  • Two binding site effects observed in receptors (e.g., nicotinic ACh receptor).

Receptor Families

  • Main families include:

    1. Intracellular receptors (small molecules).

    2. Ligand-gated ion channels.

    3. Receptor with intrinsic enzymatic activity.

    4. Receptors linked to soluble kinases.

    5. G-protein-coupled receptors (GPCRs).

G Protein-Coupled Receptors

  • GPCR structure: seven membrane-spanning helices.

  • Coupling to G proteins transduces signals based on agonist binding, affecting second messenger generation.

Agonist Bias at GPCRs

  • Bias Concept: Different pathways activated by various agonists leads to potential reduced side effects in drug design.

  • Example: TRV130 showcases reduced adverse effects compared to traditional agonists.