Designing new treatments for depression and anxiety
DOV Pharmaceutical Inc, Somerset, NJ 08873-4185, USA.IDrugs: the investigational drugs journal (Impact Factor: 2.33). 04/2008; 11(3):189-97.
Depression and anxiety are disabling disorders that affect many individuals. Drugs that interfere with the reuptake and/or metabolism of biogenic amines have been used to treat depression for more than four decades. An important development in the treatment of depression has been the emergence of triple reuptake inhibitors (SNDRIs), which inhibit the reuptake of serotonin, norepinephrine and dopamine. Preclinical and clinical research indicates that drugs inhibiting the reuptake of all of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants. Allosteric modulation of GABAA receptors can produce anxiolytic, sedative/hypnotic and anesthetic effects, presumably from enhancing the inhibitory neurotransmission of GABAA through a facilitation of receptor function. Benzodiazepines have been used with great success as anxiolytics, but the use of these drugs is limited because of their addictive potential and sedative side effects. This feature review discusses the design and synthesis of antidepressants based on the monoamine hypothesis of depression, and presents the current status of research on GABAA receptor modulators as a potential treatment for anxiety disorders.
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ABSTRACT: In the past decades considerable evidence has emerged that certain so called neuroactive steroids not only act as transcription factors in the regulation of gene expression but may also alter neuronal excitability through interaction with specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)), N-methyl-D-aspartate (NMDA) and glutamate receptors. There is growing evidence that neuroactive steroids play an important role as endogenous modulators of neuronal function and behavioural processes and that alterations of endogenous neuroactive steroid concentrations may contribute to the pathophysiology of affective disorders. In view of their positive allosteric potential at GABA(A)-receptors, especially 3alpha-reduced neuroactive steroids have been suggested to play a major role in the pathophysiology of anxiety disorders. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. Therefore, attenuation of neuroactive steroid concentrations either by synthetic derivates of neuroactive steroids or by modulation of endogenous neurosteroid synthesis might constitute a promising novel strategy for the treatment of anxiety disorders. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.
Article: Potential Novel Anxiolytic Drugs[Show abstract] [Hide abstract]
ABSTRACT: Anxiety disorders are common and disabling conditions. Current drug treatment methods have limitations including resistance, delayed efficacy and side effects. The advent of sophisticated imaging techniques and the production of highly selective receptor ligands have increased our knowledge of the biological mechanisms underpinning anxiety. Our aim is to review recent discoveries in important neurological systems to provide an understanding of important current anxiolytic targets. Some of these systems, such as GABA, have been implicated in anxiety disorders for decades, but a recent greater understanding is enabling more sophisticated targeting of treatments. In other systems, including the neuropeptides, we have now developed the pharmacological tools in human subjects to begin exploring their relationship to anxiety disorders. We review GABA, serotonin, glutamate, noradrenaline, dopamine and some neuropeptides herein.
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ABSTRACT: It is important to gain more insight into neurodegenerative diseases, because these debilitating diseases can not be cured. A common characteristic of many neurological diseases is neuroinflammation, which is accompanied by the presence of activated microglia cells. In activated microglia cells, an increase in the expression of peripheral benzodiazepine receptors (PBR) can be found. The PBR was suggested as a target for monitoring disease progression and therapy efficacy with positron emission tomograpy (PET). The PET tracer [(11)C]PK11195 has been widely used for PBR imaging, but the tracer has a high lipophilicity and high non-specific binding which makes it difficult to quantify uptake. Therefore, efforts are being made to develop more sensitive radioligands for the PBR. Animal studies have yielded several promising new tracers for PBR imaging, such as [(11)C]DAA1106, [(18)F]FEDAA1106, [(11)C]PBR28, [(11)C]DPA713 and [(11)C]CLINME. However, the potential of these new PBR ligands is still under investigation and as a consequence [(11)C]PK11195 is used so far to image activated microglia cells in neurological disorders. With [(11)C]PK11195, distinct neuroinflammation was detected in multiple sclerosis, Parkinson's disease, encephalitis and other neurological diseases. Because neuroinflammation plays a central role in the progression of neurodegenerative diseases, anti-inflammatory drugs have been investigated for therapeutic intervention. Especially minocycline and cyclooxygenase inhibitors have shown in vivo anti-inflammatory, hence neuroprotective properties, that could be detected by PET imaging of the PBR with [(11)C]PK11195. The imaging studies published so far showed that the PBR can be an important target for monitoring disease progression, therapy response and determining the optimal drug dose.
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