Medicinal Chemistry of Antidepressant Agents

Vocabulary practice flashcards covering neurotransmitter biosynthesis and metabolism, MAOIs, SSRIs, TCAs, SNRIs, and miscellaneous antidepressant mechanisms based on PHAR 441 lecture notes.

Monoamine Hypothesis of Depression

A hypothesis proposing that depression is related to a deficiency in the amount or function of cortical and limbic monoamine neurotransmitters: Norepinephrine (NE), Dopamine (DA), and Serotonin ($5\text{-HT}$).

Tyrosine Hydroxylase (TH)

The rate-limiting enzyme in catecholamine biosynthesis that catalyzes the conversion of L-Tyrosine to L-Dihydroxyphenylalanine (L-Dopa).

L-Aromatic Amino Acid Decarboxylase (AADC)

An enzyme involved in monoamine synthesis that converts L-Dopa to Dopamine (DA) in catecholamine biosynthesis, and converts $5\text{-Hydroxytryptophan}$ ($5\text{-HTP}$) to Serotonin ($5\text{-HT}$) in serotonin biosynthesis.

Dopamine $\beta$-Hydroxylase (DBH)

The enzyme in the catecholamine biosynthetic pathway that converts Dopamine (DA) into Norepinephrine (NE).

Phenylethanolamine N-methyltransferase (PENMT)

The enzyme that catalyzes the final step in catecholamine synthesis, converting Norepinephrine (NE) into Epinephrine (E).

Vanillylmandelic Acid (VMA)

$3'\text{-Methoxy-}4'\text{-hydroxy-mandelic acid}$, a major end-product of Norepinephrine (NE) and Epinephrine (E) metabolism produced by the action of MAO and COMT.

Tryptophan Hydroxylase

The rate-limiting enzyme in serotonin biosynthesis that hydroxylates Tryptophan to form $5\text{-Hydroxytryptophan}$ ($5\text{-HTP}$).

Selegiline

An irreversible, selective MAO-B inhibitor at lower doses that crosses the blood-brain barrier without causing the hypertensive "cheese effect"; its transdermal formulation (EMSAM) is approved for depression, and its metabolism via N-dealkylation yields amphetamine and methamphetamine.

Phenelzine

A phenylethylhydrazine-derivative antidepressant that functions as a non-selective, irreversible mechanism-based monoamine oxidase inhibitor (MAOI).

Tranylcypromine

A non-selective irreversible mechanism-based MAOI that forms a benzylic free radical reactive species, retains amphetamine-like properties, causes immediate CNS-stimulant effects, and induces the hypertensive "cheese effect".

MAOI Washout Period

A required 2-week waiting period after discontinuing an irreversible MAO inhibitor before starting another serotonergic agent, necessary because enzyme inactivation persists until new MAO is resynthesized.

Fluoxetine

A selective serotonin reuptake inhibitor (SSRI) metabolized by $\text{CYP2D6}$ via N-demethylation into its active metabolite, Norfluoxetine; it also reversibly inhibits $\text{CYP2D6}$.

Paroxetine

An SSRI metabolized by $\text{CYP2D6}$ via O-demethylation and oxidation to a catechol and reactive quinone species, resulting in irreversible, mechanism-based inhibition of $\text{CYP2D6}$.

Escitalopram

The pure $(S)\text{-(+)}$ enantiomer of citalopram, which contains all of the desired antidepressant therapeutic activity found in racemic citalopram.

Tricyclic Antidepressants (TCAs) SAR

Structural class defined by two aromatic rings joined by a central ring in a 6-7-6 system connected to an aliphatic amine by 2–3 carbons; dimethyl-amino compounds favor SERT inhibition and sedation, whereas monomethyl-amino compounds favor NET inhibition and stimulation.

Imipramine

A tertiary (dimethyl-amino) tricyclic antidepressant structurally related to phenothiazines that blocks SERT more than NET, possesses anticholinergic and sedative properties, and is metabolized by N-demethylation into desipramine.

Desipramine

A secondary (monomethyl-amino) tricyclic antidepressant and active metabolite of imipramine that acts as a selective norepinephrine reuptake inhibitor (SNERI or NET inhibitor) with lower sedative and anticholinergic effects.

Amitriptyline

A dimethyl-amino TCA that functions as a SERT inhibitor with prominent sedative and anticholinergic effects; inactivated by hydroxylation at the benzylic 10-position and metabolized via N-demethylation to nortriptyline.

Nortriptyline

A monomethyl-amino TCA and active metabolite of amitriptyline that functions as a NET inhibitor (SNERI) and has reduced sedative and anticholinergic activity.

Venlafaxine

A non-tricyclic serotonin-norepinephrine reuptake inhibitor (SNRI) that undergoes O-demethylation by $\text{CYP2D6}$ to yield its major active metabolite, Desvenlafaxine.

Duloxetine

A non-tricyclic serotonin-norepinephrine reuptake inhibitor (SNRI) used as an antidepressant.

Trazodone

An antidepressant that acts as an SSRI and $5\text{-HT}_{2\text{A}}$ receptor antagonist, reducing SSRI-mediated side effects; metabolized via N-dealkylation to mCPP.

m-Chlorophenylpiperazine (mCPP)

A active metabolite of trazodone that functions as a potent $5\text{-HT}_{2\text{A}}$ antagonist and research probe for serotonin function, which has also been identified as a street drug of abuse.

Buspirone

An anxiolytic and antidepressant partial agonist at $5\text{-HT}_{1\text{A}}$ receptors (acting presynaptically to diminish $5\text{-HT}$ release in anxiety and postsynaptically to stimulate receptors when $5\text{-HT}$ levels are low); its N-dealkylation does not generate mCPP.