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Jack DeRuiter, Principles of Drug Action 2, Fall 2001 DRUGS THAT ALTER DOPAMINE NERVE STRUCTURE OR FUNCTION MC Objective: Characterize the chemical and pharmacologic properties of "DA releasers" such as Amantadine and the amphetamines) NH2 Amantadine • • • • • • • • Amantadine is a basic amine (pKa 10.8) and predominantly ionized at physiologic pH. Amantadine has a lipophilic carbon "cage structure" that enhances tissue penetration and sterically blocks metabolism (no AMO or other deamination metabolism) Amantadine promotes DA release from presynaptic nerves (activity is dependent on intact and functional DA nerves. Its activity is enhanced when administered with LDOPA (greater DA formation)! Amantadine also delays the reuptake of DA in functional DA nerves Amantadine has a rapid onset : within 2 weeks Amantadine has lower efficacy (because of its mechanism of action) but fewer side effects that L-DOPA Amantadine is eliminated unchanged renally and therefore should be used with caution in renal impairment (reduce dose!) Amphetamines (see structures below) can release DA, as well as inhibit DA reuptake and weakly block MAO metabolism by competitive inhibition this enzyme. MC Objective: Characterize the chemical and pharmacologic properties of inhibitors of DA release (GHB and its lactone) HO HO O Gamma-Hydroxybutyric Acid (GHB) • • O O Butyrolactone GHB and its lactone form specifically block DA release (not other NTs) by an unknown mechanism This drug, particularly in its lipophilic lactone form can pass biologic membranes including the BBB 1 Jack DeRuiter, Principles of Drug Action 2, Fall 2001 MC Objective: Characterize the chemical and pharmacologic properties of the natural product Reserpine (from Rauwolfia serpentina), a DA depletor N N H H H OCH3 H CH3OOC OOC H OCH3 OCH3 OCH3 Reserpine • • • • • • • Reserpine depletes NE from dopaminergic (and adrenergic and serotonergic nerves) by inhibiting the Mg-ATPase transporter responsible for sequestering DA (and NE and 5-HT) in storage vesicles. The DA not stored is largely metabolized by MAO. This results ultimately in depletion of intraneuronal stores of neurotransmitter. Based on its mechanism of action, reserpine has been used for the treatment of schizophrenia and hypertension. Reserpine is used only infrequently now because its non-specific acxtions result in an array of undersired peripheral and central side effects. Reserpine in solution may undergo hydrolysis, indole decomposition (light-mediated) and epimerization. Show the epimerization product and why it occurs. Reserpine readily passess the BBB by diffusion and enters the CND due to it's lipophilicity. Why does the duration of action of reserpine exceed its plasma half-life? Reserpine is metabolized by esterase-mediated hydrolysis and oxidative Odemethylation. Propose structures for these metabolites. MC Objective: Characterize the chemical and pharmacologic properties of the inhibitors of DA reuptake: Note that the structures required to block DA reuptake differ significantly from those required to block NE or 5-HT reuptake! O NHR H S N CH(CH ) 32 CH3 CH3 R = H: Amphetamine R = CH3 : Methamphetamine Cl N CH3 N CH3 CH3 CH2CH3 Bupropion Tandamine H3C N O N CH3 NH2 COOCH3 Nomifensine O Cocaine (and related compounds) 2 Jack DeRuiter, Principles of Drug Action 2, Fall 2001 • • • Many of these drugs have multiple pharmacologic actions (amphetamines and cocaine) in addition to inhibition of DA reuptake. Cocaine primarily is a drug of abuse that has a short half-life due to rapid metabolic inactivation by ester hydrolysis and OND The actions of some the DA reuptake inhibitors (Bupropion and Nomifensine) will be covered in more when inhibition of NT reuptake is discussed generally. MC Objective: Characterize the chemical and pharmacologic properties of compounds capable of destroying DA neurons. • • 6-Hydroxydopamine and xylamine are DA depletors in PNS (except the adrenal medulla) and CNS Irreversibly destroy sympathetic and DA neurons via formation of reactive metabolites that are capable of alkylating nucleophilic residues on nerve enzymes and proteins and rendering the nerve non-functional: OH O NH2 NH2 [O] HO HO OH O 6-Hydroxydopamine "Reactive Quinone" Destruction of DA nerve terminals Cl Chemical N CH3 Xylamine • CH3 N CH3 CH3 Aziridnium Ion MPTP is a by-product or contaminant in the synthesis of the narcotic MPPP (meperidine analogue referred to as "designer heroin" 1. MPTP binds selectively to MAO-B which is highly concentration in the SN 2. Glial and 5-HT cells convert MPTP to MPDP+ which can diffuse iout an disproportionate to MPP+ 3. DA and NE terminals accumulate MPP+ through catecholamine uptake. 4. Neuromelanin of SN neurons bind MPP+ 5. MPP+ rapidly accumulates in mitochondria where it inhibits NADH dehydrogenase resulting in ATP depletion and cell death 3 Jack DeRuiter, Principles of Drug Action 2, Fall 2001 Bioactivavtion of MPPP and DA Neuronal Death O Elimination O C3H7 MAO-B -OOCC3H7 H N N N CH3 CH3 CH3 MPPP ("Designer heroin") OH MPTP H2O MAO-B H2O N H HO CH3 N N CH3 CH3 + MPP + MPDP 4