Medchem EXAM 4

Catecholamines Overview

• Catecholamines are key neurotransmitters that are crucial to the fight-or-flight response

• Include dopamine, norepinephrine, and epinephrine
  1. Can all participate in hydrogen bonding as well as aromatic stacking and pi-pi interactions
  2. All contain amino groups that are predominantly ionized at physiological pH

• Catecholamine neurotransmitters (CNTs) are synthesized in the neuronal cell body and can undergo axonal transport. Local anesthetics that block neurotransmission can therefore also inhibit CNT transmission

Catecholamine Biosynthesis

• First two steps take place in the neuronal cytoplasm of neurons and adrenal medulla

• All catecholamines originate from tyrosine

• Step 1: The enzyme tyrosine hydroxylase converts tyrosine into L-DOPA

• Step 2: The enzyme aromatic l-amino acid decarboxylase converts L-DOPA into dopamine
  1. Half of this dopamine gets transported from the cytoplasm into storage vesicles, while the other half continues biosynthesis

• Step 3: The enzyme dopamine B-hydroxylase converts dopamine to norepinephrine

• Step 4: The enzyme phenylethanolamine-N-methyltransferase converts norepinephrine to epinephrine. SAM acts as the methyl donor for this process

Catecholamine Receptors

• Dopaminergic system and dopamine receptors- dopamine

• Adrenergic receptors- norepinephrine and epinephrine
  1. CNT binding to adrenergic receptors is weak and reversible

Adrenergic Nervous System

• Branch of the autonomic nervous system in which epinephrine and norepinephrine (NE) are the predominant neurotransmitters

• E and NE are inactivated by the enzymes monoamine oxidase (MOA) and catechol-o-methyltransferase (COMT)

• Plays a role in regulating blood pressure, heart rate, GI motility, and bronchial tone

• Primary mechanism for the termination of NE is reuptake into the neuron

• All adrenergic receptors are GPCRs, separated into alpha and beta subtypes
  1. All B-adrenergic receptors stimulate adenyl cyclase and therefore increase cAMP levels
  2. All a2-adrenergic receptors inhibit adenyl cyclase
  3. Stimulation of B2-adrenergic receptors in the lungs causes smooth muscle relaxation and bronchodilation

• Direct Acting Adrenergic Agents- Agonists that interact directly at the adrenergic receptor

• Indirect Acting Adrenergic Agents- Cause the release of neurotransmitters

• Multiple receptor subtypes lead to many side effects upon activation

Adrenergic Nervous System Structure-Activity Relationship

• Large substituents on the amino group of a CNT results in increased B-receptor activity and decreased a-receptor activity

• Therefore, smaller substituents on the amino group of a CNT results in increased a-receptor activity

• Substitution of a small alkyl group on the B carbon adjacent to the amino group will result in inhibition of MOA

• Substitution of a hydroxyl group at this B carbon enhances both a and B activity but can decrease lipophilicity, leading to less CNS distribution

Adrenergic Agonist Effects

• Agonist binding at the following receptors will produce the listed effects:
  1. a1 receptors- smooth muscle contraction and mydriasis
  2. a2 receptors- mixed smooth muscle effects
  3. B1 receptors- increased cardiac chronotropic and inotropic effects, rise in cAMP
  4. B2 receptors- bronchodilation
  5. B3 receptors- increased lipolysis

• Epinephrine is a potent agonist at both a and B receptors, but is ineffective orally due to weakness against gastric metabolism

• Clonidine is a widely-prescribed a-adrenergic agonist used to treat hypertension, cancer pain, and withdrawal symptoms

• Ephedrine can be both a direct and indirect acting a and B agonist and has good BBB penetration. Can be used to treat hypotension. Pseudoephedrine treats nasal congestion

Adrenergic Antagonist Effects

• a-adrenergic antagonists can be used to treat BPH, hypertension, etc. Also known as a-blockers

• B-adrenergic antagonists (beta blockers!) can also treat hypertension, and are much more widely used than a-blockers

• Propanolol is a predominant beta blocker used to treat hypertension and can also treat tachycardia

Parkinson’s Disease Overview

• Caused by a lack of dopamine

• Pathological hallmark of the disease is the presence of neuronal Lewy bodies in the substantia nigra, caused by aggregation of misfolded a-Synuclein proteins

• The metabolism of dopamine naturally produces hydrogen peroxide, which, in the presence of inadequate protective mechanisms, can generate free radicals that damage dopaminergic neurons

Parkinson’s Disease Treatment

• Pharmacological treatment falls into two major categories: anticholinergics and dopaminergics

• Levodopa, the precursor for dopamine can be combined with carbidopa, which prevents its premature breakdown, to increase dopamine levels in the brain

• Dopamine levels can also be increased by blocking its metabolism by MOA. These drugs are called MAO inhibitors (MAOi). They can be used as antidepressants and to treat Parkinson’s

• The inhibition of the metabolism enzyme COMT may lead to increased levodopa distribution into the CNS

• Start with low doses of carbidopa-levodopa and work up to avoid side effects

Mechanisms to Therapeutically Alter Chemical Neurotransmission

• Axonal Transport- Kinesins are proteins responsible for anterograde (cell body TO axon) transport and dyneins are responsible for retrograde (axon to BODY) transport. This transport is defective in diseases such as Alzheimer’s.
  1. By blocking the axonal transport of certain enzymes, some drugs can inhibit the synthesis of neurotransmitters

• Axonal Membrane- Local anesthetics can prevent depolarization of the neuronal cell membrane and therefore prevent the release of neurotransmitters at the terminal → prevent transmission of pain signals

• Uptake of Neurotransmitter Precursors- Some drugs can inhibit the uptake of the precursors to some neurotransmitters, such as choline and tyrosine, therefore increasing/decreasing the amount of neurotransmitter (SSRIs, etc.)

• Synthesis of Neurotransmitter- Drugs can either stimulate or inhibit biosynthesis of neurotransmitters

• Storage- Drugs can inhibit the storage of neurotransmitters, thereby decreasing the amount of neurotransmitter available for release

• Release- An increase in intracellular Ca ion levels is critical for neurotransmitter release. Some drugs can inhibit (Botox with ACh)/stimulate release of neurotransmitters

• Receptor Binding- Drugs can be receptor agonists, antagonists, etc.

• Post-receptor Binding Effects- Drugs can inhibit/enhance the biochemical effects elicited by receptor activation by other compounds, commonly by messing with second messenger metabolism

• Inactivation of Neurotransmitter- Can happen via neuronal reuptake, enzymatic inactivation, or diffusion away from the synapse into other cells

Cocaine Info

• Cocaine rapidly crosses the BBB and works by inhibiting the reuptake of dopamine as well as the transporter for NE and serotonin

• Causes vasoconstriction and can act as a local anesthetic

• Brain adapts to chronic use, leading to higher and higher doses needed to achieve the same effect

• The major metabolite of cocaine is benzoylecogonine (BE), which is inactive. Pharmacological attempts being made to increase the rate of this metabolism in order to prevent abuse

• Street cocaine often mixed with other harmful compounds or things like flour in order to bulk up the product and cut costs for dealers

• Can cause seizures and heart attack, lots of heart issues

• Can create even more cardiotoxic compounds when mixed with ethanol

Cannabinoid Info

• Cannabinoids mostly derived from the plant cannabis sativa, which contains over 200 active compounds
  1. The two most abundant substituents of the plant are tetrahydrocannabinol (THC) and cannabidiol (CBD)

• Endocannabinoids are substances synthesized and released in the brain that bind to two main GPCRs: CB1 in the CNS and CB2 in the CNS and periphery. These receptors occur in greater abundance in the CNS than any other GPCR. Endocannabinoids maintain cellular homeostasis and also modulate the relationship between stress and reward

• CBD has been shown to be effective treatment against Dravet and Lennox-Gastaut Sydrome, forms of drug-resistant epilepsy in children

• Synthetic cannabinoids are very dangerous, though they have effects similar to marijuana, including elevated mood, relaxation, altered perception, and symptoms of psychosis

• No comprehensive SAR exists

Methanol and Ethanol Info

• One 12oz 4-6% ethanol beer is considered the standard “drink”

• Ethanol acts on many GPCRs and gated ion-channels, primarily as a CNS depressant. Stimulates GABA (relaxing) release and inhibits NMDA (excitatory) release

• Affected by first-pass metabolism via gastric and hepatic alcohol dehydrogenases, limited to 8-10ml an hour due to a lack of NAD+, turns into a linear zero-order process (rate becomes independent of concentration). Can also be hepatically metabolized via CYP2E1 and catalase
  1. Rate limiting step of alcohol metabolism = the regeneration of NAD+ from NADH

• Use of H2-receptor antagonists like cimetidine can inhibit gastric alcohol dehydrogenase, therefore increasing ethanol bioavailability

• Antabuse (disulfiram) is a drug that inhibits CYP2E1 and alcohol dehydrogenases, resulting in accumulation of acetylaldehyde in the body if alcohol is consumed, leading to awful side effects meant to prevent abuse
  1. Some antimicrobials (like Flagyl) and sulfonylurea oral hypoglycemics can cause a disulfiram-like reaction when combined with alcohol

• Alcohol use can lead to many cancers and liver disease. It is also teratogenic and causes fetal alcohol syndrome

• Treatment of methanol and ethylene glycol poisoning includes a 10% solution of ethanol and a fomepizole bolus q12h. Ethylene glycol metabolism results in the formation of oxalic acid