antidepressants 1.tricyclic antidepressants (tcas) 2.selective serotoninreuptake inhibitors (ssris)...

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  • Slide 1
  • Antidepressants 1.Tricyclic antidepressants (TCAs) 2.Selective serotoninreuptake inhibitors (SSRIs) 3.Selective norepinephrine reuptake inhibitors (SNRIs) 4.Monoamine oxidase inhibitors (MAOIs)
  • Slide 2
  • TCA General structure TCAs Introduced in 1957 by isosteric replacement of phenothiazines S with a C- C isostere This isosteric replacement also causes a change in the numbering system Numbering begins at the first carbon next to the isosteric replacement If there is a substituent on one of the rings, then start numbering on that ring
  • Slide 3
  • Consequence on Ring Geometry
  • Slide 4
  • This has several consequences with respect to ring angles is decreased, a angle and angle is introduced causing the ring to twist dramatic decrease in affinity for the dopamine receptor; most TCAs are no longer dopamine antagonists, while a few have weak dopamine antagonism Increased affinity for the norepinephrine, serotonin presynaptic membrane transporter (Uptake-1) TCAs work by competitively inhibiting Uptake-1 for norepinephrine and serotonin TCAs are generally more selective for the norepinephrine transporter as compared to serotonin with the sole exception of clomipramine
  • Slide 5
  • SAR Features common to all TCAs include: (1) A protonatable nitrogen, (2) Two aromatic rings and (3) Approximately a 2-carbon distance between the protonatable nitrogen and an aromatic ring TCA Substitutions Not much ring substitution seen with these drugs, unsubstituted phenyl rings are equal. Removal of a phenyl ring results in total loss of activity Electron withdrawing groups are not important for activity as with the phenothiazines Electron withdrawing groups can change selectivity from norepinephrine transporter to serotonin transporter and some substitutions can result in a loss of activity (Clomipramine) The C10C11 bridge can be an ethylene or vinyl with no change in activity. In fact the C10C11 bridge is not required; breaking the ring at this point can retain activity (see SSRIs)
  • Slide 6
  • Nitrogen Substituents 1.Potency is in order: 3 > 2 > 1 amine 2.Although overall the TCAs are selective for the norepinephrine transporter (except clomipramine) the 3 amine is more selective for the serotonin transporter as compared to the corresponding 2 amine; and 2 amines are more selective for NE transporter 3.3 amines are more anticholinergic and antihistaminergic than 2 amines. In fact more bulk on the nitrogen follows the anticholinergic SAR 4.Ethyl or higher alkyl groups lead to a loss of activity and an increase in toxicities. Toxicity increases with increasing chain length 5.2 o amines antidepressant activity followed by stimulation
  • Slide 7
  • Nomenclature of Tricyclic Ring System
  • Slide 8
  • TCA Classification 1.Based on the middle ring, or ring B a)Dibenzazepines: have a nitrogen at C 5 (Imipramine, trimepramine, clomipramine, desipramine) b)Dibenzepines: no heteroatoms (Amitriptyline, nortryptiline, protryptiline) c)Other tricyclics: some have an O in the epine ring, or an O and an N, an N in the eleven position, or a 6 membered middle ring (Doxepine)
  • Slide 9
  • 2. Based on the substitution of the aliphatic nitrogen a)2 o amines: differences as discussed before (Desipramine, nortryptiline, protryptiline) b)3 o amines: differences as discussed before (Imipramine, trimipramine, clomipramine, amitryptyline, doxepine) Common TCA side effects include Adrenergic, Seretonergic, Anticholinergic, Antihistaminic, Blocker, Quinidine-like effect What angles are present here?
  • Slide 10
  • Introduction of Clomipramine in 1990 offered the psychiatrist the first drug effectively to treat obsessive-compulsive disorder (OCD) serious enough to interfere with social or occupational functions
  • Slide 11
  • Miscellaneous Tricyclic Compounds Maprotiline: The ethyl bridge forms a fourth ring (tetracyclic) resulting in skewing of the phenyl rings similar to the TCAs Doxepine: dibenzoxepine an isostere of the TCAs and all else is the same as the TCs Amoxapine: Related to dibenzoxazepine antipsychotic loxapine without para methyl group which has been used in depressed psychotics with some success. Has more dopamine antagonistsic activity than some of the other antidepressants. Loxapine, interestingly, has little to no antidepressant activity Mirtazapine: a dibenzazepine but mechanistically is not related to the TCAs at all. It is thought to be presynaptic 2 adrenergic receptor blocker that normally inhibit the release of the NE and 5-HT, thereby increasing active levels in the synapse. It also blocks post-synaptic 5-HT2 and 5-HT3 receptorsthereby enhance serotonergic neurotransmission while causing a low incidence of side effects
  • Slide 12
  • Name Brand NEUI SUI Anti-DA Anti-His amitriptyline Elavil, Endep, Tryptanol, Trepiline yes desipramine Norpramin, Pertofrane yes imipramineTofranilyes nortriptylinePameloryes protriptylineVivactilyes trimipramineSurmontilyes amoxapine Asendin, Asendis, Defanyl, Demolox, Moxadil yes doxepinAdapin, Sinequanyes clomipramineAnafranilyes
  • Slide 13
  • SSRIs and Other Antidepressants SSRIs come from breaking the TCA ring structure that decreases bulk on the phenyl end The decreased bulk probably explains why these are not antagonists at the receptors that TCAs tend to antagonize (acetylcholine, norepinephrine, histamine) The group on the phenyl ring probably explains the selectivity for the serotonin transporter Fluoxetine (Prozac) was the first SSRI type antidepressant introduced (1986). Other examples include venlafaxine and duloxetine, which are SNRIs. Venlafaxine Effexor Duloxetine Cymbalta Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
  • Slide 14
  • Citalopram and peroxetine are potent and most specific SSRIs primarily used to treat the symptoms of major depression, OCD, PTSD, panic disorder, GAD, and PMDD. Citalopram is sold as a racemic mixture, only the S-(+) enantiomer has the desired antidepressant effect. The S- (+) enantiomer is now sold as generic escitalopram. Citalopram metabolites desmethylcitalopram and didesmethylcitalopram are significantly less active (although sometimes considered as active metabolites).
  • Slide 15
  • SSRI Related Compounds Atomoxetine and Reboxetine are selective norepinephrine reuptake inhibitors (SNRIs) which are very selective for inhibiting the norepinephrine reuptake transporter (Be careful, SNRI has also been used to stand for Serotonin Norepinephrine reuptake inhibitor such as venlafaxine) These drugs lack a strong electron withdrawer on the phenyl ring that decreases selectivity for the serotonin transporter They retain a similar side effect profile except adrenergic side effects (has more adrenergic side effects than SSRIs) Atomoxetine is used in the US for ADHD and Reboxetine is used in Europe for depression These drugs dont have serotonergic side effects and, thus, decrease the risk for serotonin syndrome Atomoxetine Strattera Reboxetine Vestra
  • Slide 16
  • Basic, the cyclopropane ring is completely rigid and will dominate the 3-D structure of the drug Racemic; however, the 'active' d-isomer having a longer half-life than the 'inactive' l-isomer. The approved drug is the Hydrochloride salt SNRI in 3:1 ratio and used for the treatment of clinical depression (serotonin) and fibromyalgia (NE) Well absorbed after oral dosing (bioavailability of 85%), meals do not have an influence on the rapidity and extent of absorption Conjugated to the inactive glucuronide and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found. Enzymes of the CYP class do not play a role in the metabolism of Milnacipran so that the risk of interactions with drugs metabolized by CYP enzymes is minimal. New Molecular Entity in 2009: Milnacipran
  • Slide 17
  • Triazolopyridines contain a fused triazole ring and a pyridine ring, e.g., trazadone, which have a complex pharmacology Nefazodone is an analog The N closest to the triazole ring and the phenyl ring on the end opposite the triazolopyridine ring structure are the parts that interact with the receptor These drugs are selective inhibitors of the serotonin transporter. They are not considered to be SSRIs due to a different side effect profile They are also good blockers, and 5-HT2A antagonists Nefazodone Serzone (discontinued due to liver toxicity)
  • Slide 18
  • MAOIs Isoniazide Antitubercular but too polar Iproniazide Antitubercular but CNS stimulant Which later shown to be MAOI resulting in NE & 5-HT New antidepressant introduced but withdrawn due to liver toxicity, however, increased interest on hydrazines and hydrazides for antidepressants Thus MAOIs based on the hydrazine molecule have been extensively studied. Hydrazine, itself, has no MAOI activity Must have a free amino at one end to be active; a protonatable terminal N is necessary; those without a terminal N are prodrugs and must be bioactivated Must have at least one free hydrogen on each nitrogen Adding an alkyl group to one nitrogen of hydrazine confers MAOI activity: Ethyl is the most potent of the series methyl, ethyl, propyl, etc. Branching with a methyl group does not affect potency hydrazines
  • Slide 19
  • Ring Additions & Disubstiturions Ring Addition Adding a phenyl ring produces a compound with no MAOI activity Adding a benzyl ring confers good activity, adding a phenethyl (phenyl ethyl) ring is even more potent More closely approximat


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