Adamantanes

Amantadine

In 1993, amantadine was found to bind to the sigma σ1 receptor with relatively high affinity (Ki = 20.25 μM).[11][48] In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the sigma σ1 receptor (Ki = 7.44 μM and 2.60 μM, respectively) and that activation of the σ1 receptor is potentially involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations.[49] σ1 receptor activation is one of amantadine’s more potent actions.[11][49] σ1 receptor agonists enhance tyrosine hydroxylase activity, modulate NMDA-stimulated dopamine release, increase dopamine release in the striatum in vivo, and decrease dopamine reuptake.[11]

Amantadine has been found to increase aromatic amino acid decarboxylase expression.[11] This enzyme is responsible for the synthesis of dopamine from L-DOPA.[11] An imaging study in humans found that amantadine increased AADC activity in the striatum by up to 27%.[11]

• Potential antidepressant effect of amantadine: a review of preclinical studies and clinical trials
• Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury
• Amantadine in Treatment of Dysthymia—The Pilot Case Series Study
  • Two men and three women were treated with 100 mg amantadine for 3 months with 3–5 months follow-up. After 1 month of treatment with amantadine, a significant reduction in the intensity of depressive symptoms was achieved in all patients, and the clinical improvement increased over the next 2 months of treatment. No deterioration in well-being was observed in any patient after discontinuation of amantadine
• Effects of amantadine on circulating neurotransmitters in healthy subjects
  • 100 mg oral amantadine causes 50-70% reduction in plasma free serotonin (f5-HT) and 40-60% reduction in platelet serotonin (p5-HT) within 60-120 minutes.
  • The significant and abrupt fall of serotonin plasma levels (f5-HT) registered in this study should be attributed to the minimization of circulating adrenaline, triggered by the drug.
• Amantadine reduces glucagon and enhances insulin secretion throughout the oral glucose tolerance test: central plus peripheral nervous system mechanisms
  • Maximal reductions of plasma glucose and glucagon plus exacerbated insulin rises were significantly greater throughout the oral glucose plus amantadine test
  • The addition of an oral dose of amantadine (100 mg) to an oral glucose load enhanced the normal noradrenaline and dopamine rises
  • Both platelet serotonin (p5-HT) and plasma serotonin (f5-HT) showed maximal decreases throughout the test when an oral dose of amantadine (100 mg) was added to an oral glucose load.
• Amantadine tremor, a 5-hydroxytryptamine-mediated response?
  • An ED50 (tremor) dose of amantadine decreases the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in rat brain (by 30-50%), particularly when this is elevated due to pretreatment with 5-hydroxytryptophan.
• Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia
• The noradrenaline transporter as site of action for the anti-Parkinson drug amantadine
  • Amantadine induced NAT-mediated release at concentrations of 10e100 mM in superfusion experiments and blocked NAT-mediated cytotoxicity
  • Thus, amantadine acted as “amphetamine-like releaser” with selec- tivity for the noradrenergic system
• The effect of amantadine on prolactin levels and galactorrhea on neuroleptic-treated patients
  • Plasma prolactin levels were measured in eight of the 11 subjects, and there was a significant decrease in these levels for the group. Presumably these effects are due to amantadine’s properties as a dopamine agonist and suggest a possible use of amantadine in the treatment of neuroleptic-induced galactorrhea.

Bromantane

• Treatment of asthenic disorders in patients with psychoautonomic syndrome: results of a multicenter study on efficacy and safety of ladasten
  • The antiasthenic effect of ladasten was seen on day 3 and remained during one month after the withdrawal of therapy. We determined clinical efficacy of ladasten in regard to anxiety-depressive spectrum disorders, autonomic dystonia, sleep disorders. Ladasten therapy led to the significant increase of quality of life, which was seen not only after the end of therapy, but after the withdrawal of the drug.
• Ladasten, the new drug with psychostimulant and anxiolytic actions in treatment of neurasthenia (results of the comparative clinical study with placebo)
  • The absence of “withdrawal syndrome” after the drug withdrawal reveals the lack of addictive potential in this drug.
• The effect of bromantane on the physical work capacity of laboratory animals
  • The positive effect of bromantan (0.5-50 mg/kg) on the efficiency of physical work of mice and rats (swimming test, running on a treadmill) exceeds that of phenamine administered in optimal doses by 1.3-1.6 times. Such an effect of bromantan lasts no less than 24 h. The drug delays decrease of physical efficiency and restores it sooner in repeated extreme running loads, prevents in rats the corresponding electron-microscopic changes in the cardiomyocyte and myocyte mitochondria of the skeletal muscles.
• Effect of antiasthenic drug ladasten on the level of cytokines and behavior in experimental model of anxious depression in C57BL/6 male mice
  • Ladasten induced (more significantly than imipramine) a decrease in the level of pro-inflammatory cytokines IL-6, IL-17 and IL-4, removed behavioral changes, and restored indexes of immunity organs. Thus, the antiasthenic drug ladasten limits development of the anxious depressive state and suppresses the level ofproinflammatory cytokines IL-6, IL-17 and IL-4.
• Effects of the Novel Anti-Asthenic Drug Ladasten on Behavior and T-Cell Subsets Alterations in a Social Defeat Animal Model of Depression
  • Ladasten injections alleviated SDS behavioral effects and attenuated symptoms of depression. The defeated group that received ladasten showed behavior similar to that of non-defeated control mice, which were housed and treated similarly but were not exposed to aggressors.
  • Administration of ladasten to defeated mice prevented thymus weight loss. Although ladasten did not reverse splenomegaly, it partially restored spleen weight (by 18%). The T-lymphocyte subsets present in the blood, spleen and thymus of ladasten treated mice remained in similar proportions to those of the unstressed control animals.