Useful reading (refer to Foye s 7 th ed)

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1 Antidepressants Morten Grøtli Department of Chemistry and Molecular Biology Useful reading (refer to Foye s 7 th ed) Chaper 18, page You are expected to read these pages before you come to the lecture 1

2 eurotransmitter deficiency syndroms and their interactions Structure? Serotonine orepinephrine Dopamin 2

3 Monoamine hypothesis Serotonin nurotransmission 3

4 orephinephrine nurotransmission Types of antidepressive drugs Antidepressive drugs Monoamine reuptake inhibitors Monoamine oxidase inhibitors Miscellaneous Selective onselective 4

5 Selectivity ratios for reuptake inhibitors orephinephrine reuptake Serotonin reuptake TCA Tricyclic antidepressants B 2 C A R 1 R 2 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 umbering 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 5

6 Tricyclic antidepressants Tricyclic antidepressants α is decreased, a β angle and γ 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 (reuptake) TCA s work by competitively inhibiting reuptake for norepinephrine and serotonin TCA s are generally more selective for the norepinephrine transporter as compared to serotonin with the sole exception of clomipramine 6

7 Tricyclic antidepressants Tricyclic antidepressants 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 ot 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 C10 C11 bridge can be an ethylene or vinyl with no change in activity. In fact the C10 C11 bridge is not required; breaking the ring at this point can retain activity (see SSRIs) 7

8 Tricyclic antidepressants 1. 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 E transporter; 2. 3 amines are more anticholinergic and antihistaminergic than 2 amines. In fact more bulk on the nitrogen follows the anticholinergic SAR; 3. Ethyl or higher alkyl groups lead to a loss of activity and an increase in toxicities. Toxicity increases with increasing chain length; 4. 2 o amines antidepressant activity followed by stimulation. Tricyclic antidepressants 1. Based on the middle ring, or ring B Dibenzazepines: have a nitrogen at C 5 (Imipramine, trimepramine, clomipramine, desipramine) Dibenzepines: no heteroatoms (Amitriptyline, nortryptiline, protryptiline) ther tricyclics: some have an in the epine ring, or an and an, an in the eleven position, or a 6 membered middle ring (Doxepine) CH3 Amitryptiline Doxepine 8

9 Tricyclic antidepressants 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) H H Desipramine ortriptyline Common TCA side effects include Adrenergic, Seretonergic, Anticholinergic, Antihistaminic, α Blocker, Quinidine-like effect What angles are present here? Metabolism of clomipramine 9

10 Tricyclic antidepressants Maprotiline: The ethyl bridge forms a fourth ring (tetracyclic) resulting in skewing of the phenyl rings similar to the TCA s H 3 C Doxepine: dibenzoxepine an isostere of the TCA s and all else is the same as the TC s Cl H 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 TCA s at all. It is thought to be presynaptic 2 adrenergic receptor blocker that normally inhibit the release of the E and 5-HT, thereby increasing active levels in the synapse. It also blocks post-synaptic 5- HT2 and 5-HT3 receptors thereby enhance serotonergic neurotransmission while causing a low incidence of side effects Metabilisme of mirtazapine H Mirtazapine H + Desmethylmirtazapine 8-Hydroxymirtazapine + Mirtazapine--oxide 10

11 Selective norepinephrine reuptake inhibitors (SRI) Atomoxetine and Reboxetine are selective norepinephrine reuptake inhibitors (SRIs) which are very selective for inhibiting the norepinephrine reuptake transporter (Be careful, SRI has also been used to stand for Serotonin orepinephrine 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 don t have serotonergic side effects and decrease the risk for serotonin syndrome Metabolism of R-atomoxetine 11

12 Selective serotonin reuptake inhibitors (SSRIs) 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). ther examples include venlafaxine and duloxetine, which are SRIs. H S Venlafaxine Duloxetine Serotonin-orepinephrine Reuptake Inhibitors (SRIs) Phenoxyphenylalkylamine selective serotonin reuptake inhibitors (SSRIs) 12

13 Derivatives of fluoxetine Serotonine reuptake transporter (SERT) affinity R 2 R 2 R 1 ro H H SERT<100 SERT<10 F H Paroxetine R R R 1 H F H SERT <

14 Metabolism Phenylalkylamine SSRIs 14

15 The metabolism of sertraline Miscellaneous SSRIs 15

16 on-tricyclic reuptake inhibitors H 3 C H H 3 C H H 3 C H 3 C CH3 (+)-Venlafaxine (+)-Tramadol H 2 (+)-cis-milnacipran S (S) H H S(+)-Duloxetine Metabolism of venlafaxine 16

17 Metabolism of duloxetine Dopamine and norepinephrine reuptake inhibitors; Bupropion 17

18 Dopamine and norepinephrine reuptake inhibitors H Cl Trazodone Cl Cl Aripiprazole 6 C 5 H Serotonin reseptor modulators Cl H 2 efazodone Vilazodone (6-hydroxyl = vilazodone metabolite) Mianserin Mirtazapine 18

19 Metabolism of trazodone Metabolism of aripiprazole Cl Cl H R Cl Cl H Aripiprazole CYP3A4/ 2D6 CYP3A4 Cl CYP3A4 Cl H Dehydroaripiprazole (Active) Cl Cl H + H R' 2,3-Dichlorophenylpiperazine (DCPP) 19

20 MAI antidepresants Isoniazide Antitubercular but too polar MAI antidepresants Iproniazide Antitubercular but CS stimulant Which later shown to be MAI resulting in E & 5-HT ew antidepressant introduced but withdrawn due to liver toxicity, however, increased interest on hydrazines and hydrazides for antidepressants H 2 H 2 hydrazines Thus MAIs based on the hydrazine molecule have been extensively studied. Hydrazine, itself, has no MAI activity Must have a free amino at one end to be active; a protonatable terminal is necessary; those without a terminal 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 MAI activity: Ethyl is the most potent of the series methyl, ethyl, propyl, etc. Branching with a methyl group does not affect potency 20

21 MAI antidepresants Ring Addition Adding a phenyl ring produces a compound with no MAI activity Adding a benzyl ring confers good activity, adding a phenethyl (phenyl ethyl) ring is even more potent More closely approximates norepinephrine, serotonin and dopamine, etc H H 2 Disubstitution Phenelzine, disubstitution on one end decreases, or loses, potency MAI antidepresants Hydrazides: hydrazine with one nitrogen forming an amide, e.g., Iproniazid and isocarboxazide Isocarboxazide H H These drugs have lipophilic substituents that allow them to cross the BBB, where they are hydrolyzed to the active species. This increase the potency by allowing more drug to reach the site of action Mechanism of Action - MAIs covalently bind MA, irreversibly inhibiting the reaction. Iproniazid Phenelzine An effective mechanism-based antidepressant agent. It is presumably oxidized to diazene (H=H) (which can then break up into molecular nitrogen, a hydrogen atom), and a phenethyl free radical that would be the active species in irreversible inhibition 21

22 Competitive MAIs MAI antidepresants The present clinically useful irreversible MAIs are mechanism-based as they form reactants that covalently bond the enzyme or its cofactor Thus they may continue their action up to 2 weeks after administration is discontinued The harmala alkaloid harmaline and harmine are competitive inhibitors of MA and are CS stimulants Moclobemide has received considerable attention. It is an effective antidepressant without producing hypotensive crisis which is a reversible inhibitor of MA-A and permits metabolism of dietary tyramine, however, caution is still needed to avoid excessive intake (of cheddar cheese, feva beans) MAI antidepresants H 2 Tranylcypromine The distance from the phenyl to the amine is closer to norepinephrine The cyclopropyl group is very strained (reactive) and alkylates the enzyme The trans isomer is more potent than the cis isomer The ring is more unstable and binds the enzyme better CH C H (-)-Selegiline Has an acetylene functional group that is unstable Results in covalent bond to the enzyme Part of its metabolic fate is -dealkylation to methamphetamine Selegiline is the ( ) isomer and so it forms ( ) methamphetamine not the active (+) form as shown Selective MA-B irreversible inhibitor (at lower doses) 22

23 Lithium ion suppresses inositol triphosphate signalling Intracellular phosphatidylinositol signalling pathway and site of action for lithium 23

24 Agomelatine The first approved antidepressant to incorporate a non-monoaminergic mechanism of action. Agomelatine The first approved antidepressant to incorporate a non-monoaminergic mechanism of action. 24

25 Questions F 3 C H C. HCl D 1. Strukturerna för två läkemedel visas i Figur 2. Föreslå trolig farmakologisk effekt för varje läkemedel. 2. Läkemedel C kan metaboliseras till flera metaboliter. Rita och förklara hur tre olika metaboliter kan bildas. 3. D metaboliseras i huvudsak i levern, till den aktiva metaboliten X. Rita S-isomeren av metaboliten X. Questions Compound 2 and 3 are derivatives of compound 1. Will 2 and 3 have comparable pharmacological effect to 1? 25

26 Questions Explain how the compound can be modified in order to obtain an improved SSRI 26