PHARMACOLOGICAL EFFECTS OF (±)-, (S)-, and (R)-MDA

Marquardt, Gerald M.; DiStefano, Victor; Ling, Lydia L.

doi:10.1016/b978-0-08-021938-7.50011-4

Cited by 16 publications

(7 citation statements)

References 31 publications

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“…d ‐MDA is more potent than its l ‐isomer in causing acute neurotransmitter depletion (32, 33) and induction of acute stereotypic behavior and locomotion (34, 35). At a low dose, d ‐MDA is more potent in causing long‐term neurotransmitter depletion, but this stereo‐selectivity is lost at a higher dose (36).…”

Section: Resultsmentioning

confidence: 99%

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration ¹

et al. 2006

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Reactive oxygen species (ROS) are implicated in amphetamine-initiated neurodegeneration, but the mechanism is unclear. Here, we show that amphetamines are bioactivated by CNS prostaglandin H synthase (PHS) to free radical intermediates that cause ROS formation and neurodegenerative oxidative DNA damage. In vitro incubations of purified PHS-1 with 3,4-methylenedioxyamphetamine (MDA) and methamphetamine (METH) demonstrated PHS-catalyzed time- and concentration-dependent formation of an amphetamine carbon- and/or nitrogen-centered free radical intermediate, and stereoselective oxidative DNA damage, evidenced by 8-oxo-2'-deoxyguanosine (8-oxo-dG) formation. Similarly in vivo, MDA and METH caused dose- and time-dependent DNA oxidation in multiple brain regions, remarkably dependent on the regional PHS levels, including the striatum and substantia nigra, wherein neurodegeneration of dopaminergic nerve terminals was evidenced by decreased immunohistochemical staining of tyrosine hydroxylase. Motor impairment using the rotarod test was evident within 3 wk after the last drug dose, and persisted for at least 6 months. Pretreatment with the PHS inhibitor acetylsalicylic acid blocked MDA-initiated DNA oxidation and protected against functional motor impairment for at least 1.5 months after drug treatment. This is the first direct evidence for PHS-catalyzed bioactivation of amphetamines causing temporal and regional differences in CNS oxidative DNA damage directly related to structural and functional neurodegenerative consequences.

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Section: Resultsmentioning

confidence: 99%

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration ¹

et al. 2006

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“…Inasmuch as antibodies selected by immunization with hapten-protein conjugates are directed at parts of the molecule projecting from the protein, the molecular orientation of the hapten on the protein carrier was considered critical to the specificity of the antibodies (Landsteiner, 1962). The (ϩ)-or d-isomers of METH-like compounds produce significantly more psychomimetic effects, locomotor activity, stereotyped behavior, and monoamine oxidase inhibition than the (Ϫ)-or l-isomers (Marquardt et al, 1978;Caldwell, 1980). Thus, all METH-like haptens were synthesized to mimic the molecular features of (ϩ)-isomers of the drugs.…”

Section: Resultsmentioning

confidence: 99%

Using Hapten Design to Discover Therapeutic Monoclonal Antibodies for Treating Methamphetamine Abuse

Peterson

Gunnell²,

Che³

et al. 2007

J Pharmacol Exp Ther

106

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When generating monoclonal antibodies (mAb) against small molecules, the chemical composition and molecular orientation of the drug-like hapten on the antigen is a crucial determinant. This is especially important when attempting to discover therapeutic mAb against the drugs of abuse (ϩ)-methamphetamine, and the related compound (ϩ)-3,4-methylenedioxymethamphetamine [(ϩ)-MDMA, the plus isomer in the racemic mixture known as MDMA or ecstasy]. The goal of these studies was to design and synthesize (ϩ)-METH-like haptens with structural attributes that could make them effective for generating monoclonal antibodies for treating medical problems associated with these stimulant drugs of abuse. Five prototype (ϩ)-METH-like haptens, which mimic structural aspects of these drugs, were synthesized and used to generate mAb. After screening for anti-(ϩ)-METH IgG antibodies in more than 25,000 potential mouse hybridoma cell lines, one prototype mAb from each of the five haptens was selected and studied in detail for molecular properties and preclinical efficacy. The amino acid sequences of the IgGvariable regions, structural models, affinity, and ligand specificity of each mAb were then used to help elucidate important therapeutic characteristics. Four of these antibodies exhibited high affinity and specificity to (ϩ)-METH and (ϩ)-MDMA; whereas one antibody (designated mAb4G9) exhibited high affinity and specificity to (ϩ)-METH, (ϩ)-MDMA, and (ϩ)-AMP, without significant cross-reactivity against other METH-like ligands, over-the-counter medications, or endogenous neurotransmitters. Considered together, discovery of mAb4G9 and the other antibodies in this report represent an important step in understanding the process for custom design of drug class-specific therapeutic antibodies for the treatment of drug addiction. (ϩ)-Methamphetamine [(ϩ)-METH] abuse has becomeAmerica's number one drug threat (NACo, 2005), and effective treatment strategies for abuse of (ϩ)-METH and related stimulants are greatly needed. Current pharmacotherapies for managing the acute cardiovascular system, central nervous system, and toxic effects are mostly supportive (Sato, 1992;Albertson et al., 1999;Richards et al., 1999); they do nothing to remove the drug from its sites of action in the brain. Also lacking are medications that can reduce or treat the medically crippling effects of (ϩ)-METH addiction. Monoclonal antibodies (mAb) provide an attractive potential medication that can target the drug instead of the site of action (Kosten and Owens, 2005). These high-affinity protein-based medications act as so-called pharmacokinetic antagonists, sequestering the drug in the bloodstream away from medically vulnerable tissues, such as the brain and heart. Unlike nicotine and cocaine where the effects are caused by a single, specific compound, drugs such as opiates (e.g., morphine), arylcyclohexylamines (e.g., phencyclidine) and amphetamines [e.g., (ϩ)-METH] are starting structures from which many pharmacologically similar compounds can be synthesize...

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“…To our knowledge this is the first time that this type of action has been demonstrated for 1, although its effects on catecholamines have, been previously reported. 16,19,36,38 The relative rates also indicate that the isomers of 1 are slightly more potent in inducing release of 5-HT than are the isomers of 3. While these studies do not prove the hypothesis that the (+) isomer of MDMA (2) owes it's in vivo biological activity to transmitter release, the data are consistent with this hypothesis.…”

mentioning

confidence: 99%

Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes

Nichols¹,

Lloyd²,

Hoffman³

et al. 1982

J. Med. Chem.

174

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The enantiomers of 3,4-(methylenedioxy)amphetamine (MDA), p-methoxyamphetamine (PMA), and N-Me-MDA (MDMA), along with their alpha, alpha-dimethylated derivatives, were evaluated for an effect on the release of [3H]serotonin from rat whole brain synaptosomes. The amphetamine isomers were all potent in inducing the release of [3H]serotonin at bath concentrations of 1 and 10 micrometers but were inactive at 0.1 micrometers. No significant difference in isomer potency was observed at the 10 micrometers concentration. However, at 1 micrometer the (+) isomer of MDMA was more effective in inducing release than was the (-) isomer. Since it is the (+) isomer which is clinically active, this result suggests that transmitter release may play a role in the biological activity of MDMA. By contrast, the alpha, alpha-dimethyl compounds were not effective in releasing serotonin, even at the highest bath concentration.

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PHARMACOLOGICAL EFFECTS OF (±)-, (S)-, and (R)-MDA

Cited by 16 publications

References 31 publications

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration ¹

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration ¹

Using Hapten Design to Discover Therapeutic Monoclonal Antibodies for Treating Methamphetamine Abuse

Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes

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PHARMACOLOGICAL EFFECTS OF (±)-, (S)-, and (R)-MDA

Cited by 16 publications

References 31 publications

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration 1

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration 1

Using Hapten Design to Discover Therapeutic Monoclonal Antibodies for Treating Methamphetamine Abuse

Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes

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Product

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Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration ¹

Prostaglandin H synthase‐catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration ¹