Antidepressants and Benzodiazepines

• Palm Beach Atlantic University: Medicinal Chemistry
• PRX 3254- Antidepressants and benzodiazepines
• Christiane Chbib PharmD, PhD

Objectives

• Need to know the chemical structures of endogenous ligands that are implicated in depression & anxiety
• Need to recognize the chemical structures of tricyclic antidepressants, benzodiazepines, and other drug classes
• Need to understand the importance of structure activity relationship (SAR) of antidepressants to biological activity
• Need to describe the effect of chemical structures on absorption and bioavailability
• Need to identify functional groups and moieties of drug structures that lead to the metabolites

Classes of Antidepressants

• Includes tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and atypical anti-depressants
• Tricyclic anti-depressants (TCAS) include Imipramine, desipramine, nortriptyline, protriptyline, amitriptyline, and doxepin
• Monoamine oxidase inhibitors (MAOIs) include Phenelzine, selegiline, and tranylcypromine
• Selective serotonin reuptake inhibitors (SSRIs) include Fluoxetine, sertraline, paroxetine, citalopram, and escitalopram
• Serotonin norepinephrine reuptake inhibitors (SNRIs) include Venlafaxine, desvenlafaxine, and duloxetine
• Atypical anti-depressants include Duloxetine, venlafaxine, mirtazapine, and trazodone

Benzodiazepines for Anxiety and Sleep Disorder

• Gamma-Aminobutyric acid (GABA) agonists
• Benzodiazepines include Clonazepam, quazepam, Diazepam, Lorazepam, Alprazolam, and Temazepam

Structure of the Serotonin Transporter (SERT)

• SERT is a member of the neurotransmitter sodium symporter (NSS) family of transporters
• The structure of human SERT bound to (S)-citalopram molecule was found exhibits an outwards-open conformation with the drug bound to the central site, halfway across the membrane
• A second (S)-citalopram molecule was found in the allosteric site which blocks the drug's release from the central site

How Anti-depressant Interact with SERT

• There are two binding sites on SERT: central and allosteric
• Binding to the allosteric site slows the dissociation of the inhibitor from the central site

Structural Similarity of Endogenous Neurotransmitters and Ligands Implicated in Depression and Anxiety

• Ligands are endogenous
• The ligands include Phenyl, Indolamine, and Catecholamines

Structure Activity Relationship of Tricyclic Antidepressants (TCAs)

• Central ring (B): made up of 7C or 8C
• Two aromatic rings (A & C): held in skewed arrangement by a third central ring (B)
• Side chain: 3 Carbon or sometimes 2 Carbon monomethyl or dimethyl substituted aliphatic, amino group attached to position 5
• 3 carbon atoms for optimal activity
• Presence of 4 carbon atoms or branching decreases activity
• Amino group is tertiary or secondary
• methyl substituents on amino group increase activity
• Substituents larger than methyl such as ethyl reduce activity and increases toxicity

TCAS SAR continued

• Replacing N atom at 5- position with C atom does not affect activity
• 3-chloro and 10-methyl improve activity
• C9-C10 bond may be saturated or unsaturated
• Removal of one of the benzene ring from the tricyclic structure makes it inactive

Tricyclic Anti-depressants (TCAS)

• Block histamine (H1), muscarinic, and α₁ adrenergic receptors
• Cause MORE sedation and more anticholinergic side effects, more weight gain and more heart disturbances
• Cause LESS sedation and less anticholinergic side effects, less weight gain and less heart disturbances
• These include tertiary amines such as Amitriptyline(Elavil®) , Imipramine, Trimipramine, Doxepin, and Clomipramine and secondary amines such as Desipramine, Nortriptyline (Pamelor®), and Protriptyline

Metabolism of Amitriptyline

• The major metabolites is followed by conjugation with glucuronic acid
• Metabolites are mainly excreted in the urine
• Another metabolic pathway is N-oxide formation

MAO-B Inhibitors

• Due to dietary-drug interactions, MAOIs are usually reserved as a last line of treatment when other classes of antidepressant drugs have failed
• These include Rasagiline, Selegiline, Phenelzine, and Tranylcypromine
• Rasagiline and Selegiline are MAO-B selective. They are irreversible inhibitors with a low bioavailability of 10–36% and P450 metabolism
• Phenelzine and Tranylcypromine are MAO-A/B non-selective and Irreversible inhibitors

Selective Serotonin Reuptake Inhibitors (SSRIs)

• These include Dihydrobenzofuran carbonitrile and Di-hydro-benzo-furan carbo-nitrile
• (±)-Citalopram (Celexa®)
• ---Benzo
• ---nitrile
• ---dihydroFuran
• (+)-Escitalopram (Lexapro®) ----These are endogenous ligands and include Serotonin. They are An indolamine
• Selective Serotonin Reuptake Inhibitors include Paroxetine, Citalopram, Sertraline, and Fluvoxamine
• SSRIs are developed because of the need for drugs that are different from TCAs with:
• High affinity and selectivity for the SERT
• Low affinity for receptors that cause adverse effects of TCAs (5-HT, histamine, adrenergic receptors)
• No inhibition of fast sodium channels that cause cardiotoxicity associated with TCAS
• Members are not chemically related to each other, hence, if a patient does not respond to one SSRI, they may respond to a different SSRI

Paroxetine, Fluoxetine, and Sertraline

• Fluoxetine and Sertraline have active metabolites
• Fluoxetine have long half-life (avg 50 hours)
• Fluoxetine is Marketed as a racemic mixture
• The Trifluoromethyl group is at 4-para position of phenoxy group with an electron-withdrawing group and results in selective inhibition of 5-HT reuptake

Atypical Anti-depressants

• Each works in different ways from one another
• Mirtazapine(Remeron®) ----This is simply, a tetracyclic anti-depressant
• Bupropion(Wellbutrin®): ----It is an unicyclic antidepressant and also effective in treating tobacco addiction

Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

• All SNRIs inhibit serotonin (SERT) and Norepinephrine (NET)
• The medications are Venlafaxine, Desvenlafaxine, and Duloxetine.

5HT2 Antagonists

• The medications are Trazodone and Nefazodone

Gamma-Aminobutyric Acid (GABA) Agonists - Benzodiazepines

• Benzodiazepines and barbiturates are GABA agonists increasing the frequency of chloride channels and hyperpolarization of the membrane
• The GABA includes Benzodiazepines, Flumazenil, and Zolpidem
• Pharmacophore Benzodiazepine: benzene ring fused to 1 seven Membered ring containing two nitrogen

Benzodiazepines SAR

• Source of active metabolites (methyl in temazepam and diazepam)
• 2nd position KETO group is in most BZD is active (i.e. diazepam) or NH2 or N(CH3)2 like chlordiazepoxide
• 3rd position substitution leads to decreased activity; 3-OH has rapid excretion because it is polar and ready to be excreted through glucuronidation so decrease in DOA; nonpolar undergo hepatic and active metabolite which increases DOA
• 4th non-oxide are more active; unsaturation at 4-5 position is essential for activity 5th position substitution of phenyl ring at ortho or di-ortho with EWG increases activity, whereas para substitution decreases activity
• 7th position with electronegative group (Cl or nitro) increases activity (substitutions of 6, 8, and 9 decreases activity)
• Cyclization of 1-2 bond with an electron rich ring like triazole /imidazole yields high affinity and decreased half life
• Katzung 14th ed
• Benzodiazepines include Clonazepam, Diazepam, Lorazepam, Nitrazepam

Gamma-Aminobutyric Acid (GABA) Agonists - Benzodiazepines

• Fused BZD with either triazole or imidazole -Alprazolam -Triazolam -Flurazepam -Temazepam -Midazolam

What impacts the substitution on 5th position have?

• Phenyl ring at 5th position

Benzodiazepines Pharmacokinetics and Metabolism

• Slow Elimination Rates (all have active metabolites): Temazepam
• Chlordiazepoxide (Librium)
• Diazepam (Valium)
• Flurazepam (Dalmane)
• Clorazepate (Tranxene)(half life more than 24h)
• Quazepam (Doral)
• Prazepam (Currently unavailable in the US)
• Intermediate Elimination Rates:
• Alprazolam (Xanax)
• Lorazepam (Ativan)
• Clonazepam (Klonopin)(half life 12-24h)
• Oxazepam (Serax)
• Temazepam (Restoril)
• Estrazolam (ProSom - discontinued)
• Rapid Elimination Rates:
• Midazolam (Versed)(half life less than 12 h)
• Triazolam (Halcion - discontinued)
• Because of high abuse potential