CBNS 125 introduction

What is pharmacology

The study of how drugs affect the body and its functions, including mechanisms and drug actions.

What is a drug?

A molecule that causes a biochemical or physiological effect on the cell, tissue, organ, or organism.

• can be man-made, natural, or endogenous

what is neuropharmacology?

the study of drug-induced changes on the CNS and PNS

What is psychopharmacology?

study of psychoactive drugs and the effects of drugs on the psyche.

includes behavioral pharmacology

How do ligand and receptors interact?

a ligand releasing cell will release ligands, which bind to specific receptors, causing a response in the cell that contains the receptors.

What happens when there is no receptors for ligands to bond to?

If a cell does not contain receptors for the ligand to bond to, then there is no response.

Who is Paul Ehrlich

Goal: to find chemical substances which have special

affinities for pathogenic organisms

• Linked these chemicals with arsenic sidechains

• “Magic Bullets”

• Treatment for Syphilis

• Salvarsan – Introduced in 1910

What sites of the nervous system can drugs affect?

Enzymes, receptors, ion channels, nuclear receptors, DNA

What are the different kinds of bonds between receptors and drugs, and order them from weakest to strongest.

Weakest: van der Waals, Hydrogen, ionic, covalent - strongest

What kind of receptor is this? What are the sites of drug receptor interaction and resultant action?

Transmembrane ion channel

Drug receptor interaction site: extracellular, intrachannel, intracellular

Resultant action site: cytoplasm

What kind of receptor is this? What are the sites of drug receptor interaction and resultant action?

Transmembrane linked to intracellular G protein

Drug receptor interaction site: extracellular, intramembrane

Resultant action site: cytoplasm

What kind of receptor is this? What are the sites of drug receptor interaction and resultant action?

Transmembrane w/ enzymatic cytosolic domain

Drug receptor interaction site: extracellular

Resultant action site: cytoplasm

What kind of receptor is this? What are the sites of drug receptor interaction and resultant action?

Intracellular

Drug receptor interaction site: cytoplasm, nucleus

Resultant action site: cytoplasm, nucleus

What kind of ion channel is this? What is the mechanism of activation and function?

Second messenger-regulated

mechanism of action: ligand binds to transmembrane receptor w/ G protein-coupled cytosolic domain → second messenger generation

function: second messengers regulate ion conductance of channels

What kind of ion channel is this? What is the mechanism of activation and function?

ligand gated

mechanism of action: binding of ligand to channel

function: altered ion conductance

What kind of ion channel is this? What is the mechanism of activation and function?

voltage gated

mechanism of action: change in transmembrane voltage gradient

function: altered ion conductance

How do transmembrane G-protein coupled receptors (GPCRs) work?

What are the major G-alpha protein families?

G_s, G_i, G_o, G_q, G_12/13

What is the action of G_s?

directly activates adenylyl cyclase

What is the action of G_i?

directly inhibits adenylyl cyclase

What is the action of G_o?

indirectly inhibits Ca²⁺ channels and activated K⁺ channels

What is the action of G_q?

directly activates phospholipase C

What is the action of G_12/13?

directly affects motility/contractility machinery (e.g. Rho activation)

What is GPCR signaling convergence?

Where two difference receptors that have opposite effects may negate each other in the cell due to a limited number of mechanisms used to transduce intracellular signal cascades. Cancelling out effects.

What kind of transmembrane receptor with enzymatic cytosolic domain is this?

receptor tyrosine kinases (insulin receptor)

What kind of transmembrane receptor with enzymatic cytosolic domain is this?

receptor tyrosine phosphatase (immune system receptor tyrosine phosphates)

What kind of transmembrane receptor with enzymatic cytosolic domain is this?

nonreceptor tyrosine kinases

What kind of transmembrane receptor with enzymatic cytosolic domain is this?

receptor serine/threonine kinases (TGF-β receptor superfamily)

What kind of transmembrane receptor with enzymatic cytosolic domain is this?

receptor guanylyl cyclases (B-type natriuretic peptide receptor)

what’s happening in part A?

lipophilic molecules diffuse thru plasma membrane and bind to intracellular transcription factors

what’s happening in part b?

Ligand binding triggers a conformational change in the receptor (which can lead to the dissociation of a chaperone repressor protein) → transport of the ligand–receptor complex into the nucleus. In the nucleus, the ligand–receptor complex typically dimerizes.

what’s happening in part c?

The dimerized ligand–receptor complex binds to DNA and can recruit coactivators or corepressors. These complexes alter the rate of gene transcription, leading to a change (either up or down) in cellular protein expression.

what is pharmacodynamics?

A term used to describe the effects of a drug on the body.

• quantitative

  • important for dosage

  • used to compare potency, efficacy and safety

• factors include molecular interactions and integration of molecular actions

what is pharamcokinetics

Factors that influence whether a drug is successfully able to cross the physiologic barriers that limit the access of foreign substances to the body: Absorption, Distribution, Metabolism, Elimination (ADME)

What are the two methods of drug discovery?

Targeted based and phenotypic based

What is targeted based drug discovery?

used to identify a specific molecule (protein/gene) that is crucial to a disease's development

• Screen for molecules that can interact with and modify this specific target

What is phenotypic based drug discovery?

it is testing compounds on a whole cell or living organism in a disease model

• Screen for compounds that produce a desirable observable effect or therapeutic outcome