PSB3340 Ligands and Drugs

Electrical signaling vs Chemical signaling

rapid transmission of signal via ions that flow through connexon proteins connected to presynaptic membrane and postsynaptic membrane at gap junctions; NT is released into synaptic cleft which impacts the postsynaptic cell, and is slower

What makes neural signaling complex?

A NT may elicit various responses depending in target cell depending on the receptor it binds to (at one type it’s inhibitory, at another it’s modulatory, and at another it’s excitatory)

Excitatory

ligands make the target more likely to fire AP (graded potential becomes less negative)

Inhibitory

ligands make the target less likely to fire AP (graded potential becomes more negative)

Modulatory

ligand affects other cellular processes

Agonists

initiates normal effects similar to that of the NT

Partial agonists

initiates weaker version of normal effect

Inverse agonists

initiate the opposite of the normal effect, usually by reducing baseline neural activity rate

Antagonist

binds to a receptor and does not activate it, preventing other ligands from binding

Neuromodulators

Noncompetitive ligands that bind to modulatory sites that are not part of the normal receptor complex. Either activates/increases (noncompetitve agonists) or blocks/decreases (noncompetitve antagonist) effects at the receptor.

What can bind to nicotinic ACh receptors?

ACh is the endogenous ligand and nicotine is the competitive agonist (exogenous ligand) of inotropic nACh receptors

Dose Response Curve (DRC)

graph that charts the relationship between drug dose and effectsE

ED50

dose that produces 50% of the maximum effect

Potency

amount of drug needed to produce the desired effect; use ED50

Efficacy

ability of bound ligands to activate the receptor; use maximum response (not ED50) to compare

Opioids

relieve pain and produce euphoria

Endogenous ligands for opium receptors

Enkephalins and endorphins

Where do opioids bind?

At high concentrations, opioids bind to areas of the brainstem that control respiration. That’s why large doses of opioids, or small doses of very powerful ones, cause breathing issues/cessation.

Naloxone

Very potent opioid receptor antagonist. Its affinity for opioids receptors is so high that it can knock already bound agonist drugs (heroin, fentanyl, etc) off and restore proper respiration. Used for opioid overdose.

Therapeutic Index

Lethal dose (that produces effects in 50% of subjects) / effective dose (desired effects are produced). E.g. If 70 mg of morphine is lethal but 1 mg relieves pain, TI = 70/1=70. Higher = safer; lower = use with more caution. Not talking about potency or efficacy.

Bioavailable

how much drug is free to act on the target (varies with the route of digestion—snorting, orally, etc)

Blood-brain barrier

tight junctions in the CNS that prevent large molecules from moving (to enter the brain) and can limit drug availability

Intracerebral administration

bypasses the blood-brain barrier; more targeted effect than ICV but rarely done in humans

Intracerebroventricular (ICV) administration

inject directly into CSF in cerebral ventricles to bypass the blood-brain barrier (also rarely done in humans)

Functional tolerance

changes the receptor numbers, either upregulate (antagonist drug) or downregulate (agonist drug), to alter sensitivity in the opposite direction of the drug’s effect, i.e. you want to restore normal level of activity

Metabolic tolerance

organ systems become effective at eliminating the drug (e.g. drinking alcohol a lot)

Caffeine

Competitive antagonist for adenosine receptors. Adenosine promotes GABA release, which inhibits circuits involved in wakefulness when adenosine binds to them.

How do drugs alter NTs?

Changin NT production, release, or clearance

Production of NT

• Inhibit enzymes that make neurotransmitters

• Block axonal transport

• Prevent storage of NTs in vesicles

• Can also increase NT production by supplying more raw materials

  • E.g. In Parkinson’s, DA can’t cross the blood-brain barrier but l-dopa can; helps with symptoms (but it can’t make DA cross the barrier)

Release of NT

• Block Na+ (prevent AP) or Ca2+ (prevents vesicle binding/exocytosis) channels

  • Local anesthetics block Na+ channels, preventing APs and signal transmission from nociceptors (pain receptors)

    • E.g. novocain, cocaine

• Prevent release of specific NTs

• Alter autoreceptor signals

Clearance of NTs

• Blocks transporters involved in reuptake

• Inhibit enzymes that degrade NTs

  • Cocaine blocks reuptake of DA

  • Amphetamine and methamphetamine cause DA transporters to run in reverse (NT returned to synaptic cleft)

Toxins

exogenous ligands produced by other living organisms that can exert the same effect as drugs, many of which interact with ACh receptors/release

Black widow spider and ACh

Cause uncontrolled release of ACh. All ACh is released from presynaptic terminal so none are left to respond to voluntary movement commands. Targeted muscles spasm first, and then are paralyzed.

Botox and ACh

Botulium (botox) prevents release of ACh (no allowed to dock in presynaptic terminal by cutting SNARE proteins). No ACh release in targeted area prevents muscle contraction and wrinkles.