Differences Between In Vivo and In Vitro Actions

That the BZT analogues have effects in vitro that predict an effect that is generally not observed in vivo has suggested relatively poor central nervous system penetration of BZT analogues. However, a study of the pharmacoki-netics of selected BZT analogues in rats found high concentrations in the brain within minutes after injection, and that the elimination rates of BZT analogues were much slower than that for cocaine 64 . All of the BZT analogues were detected at initial concentrations...

Noradrenaline Reuptake Inhibitors

Selective inhibition of noradrenaline reuptake has been shown to be an attractive approach for the treatment of a number of diseases. For example, reboxetine 14 (Sect. 4.1.1) is used clinically for the treatment of depression and atomoxetine 13 (Sect. 4.2.1) is a new therapy for the treatment of ADHD (Fig. 30). Furthermore, NRIs are under investigation as potential therapies for chronic pain, urinary incontinence, fibromyalgia and a variety of other indications 64,65 . A number of reviews have...

NS2359GSK372475 SEP225289 Amri Cns1 2 and Acenta Series

NeuroSearch has developed potent, tropane-based uptake inhibitors 42-44 . Some of the analogs are shown in Fig. 5 and their inhibition data are shown in Table 8. NS-2359 (GSK-372475) is another triple-uptake inhibitor that went into clinical development. This compound was discovered at NeuroSearch and was subsequently licensed to GlaxoSmithKline (GSK) as part of a 5-year R& D alliance in CNS diseases. Although the structure of NS-2359 (GSK-372475) is not yet published, it is believed that...

The Dicarboxylate Amino Acid Cation Na or H Symporter Family Glutamate Transporters

Glutamate causes excitation, nudging the brain into high alert, affecting cognition and most other fundamental aspects of brain function. It transmits critical instructions between nerve cells involved in sensory perception, learning and memory. Changes in glutamate neurotransmission may contribute to different brain diseases. Glutamate has a dual action it is an excitatory neurotransmitter under normal conditions, but it is toxic to neuronal cells when present in excess. Selective modulation...

DOV 216303 DOV 21 947 and DOV 102 677

DOV Pharmaceutical Inc. is developing a series of 3-azabicyclo 3.1.0 hexanes as novel antidepressants. DOV 216 303 hydrochloride, Scheme 1 is the prototype of a class of compounds referred to as triple-uptake inhibitors 28-30 . Such compounds inhibit the uptake of 5-HT, NE, and DA, the three neurotransmitters most closely linked to major depressive disorders. The synthesis of DOV 216 303 is illustrated in Scheme 1. The described method is an optimized process for manufacturing DOV 216 303 from...

FX H

Fig. 1 Structures of tricyclic antidepressants (TCAs) Several of the early TCAs (e.g., desipramine and nortryptyline) had a high affinity for NET relative to SERT, but also possessed a high affinity at other targets associated with side effects (Table 1). Therapeutic application of moderately selective norepinephrine reuptake inhibitors, such as viloxazine, began as early as 1974, but has not demonstrated an advantage over TCAs (Fig. 2). The first selective norepinephrine reuptake inhibitor...

Norepinephrine Transporters NETs

The catecholamine norepinephrine (noradrenaline) is a neurotransmitter of the sympathetic nervous system, and as such is important in the regulation of the general degree of alertness, and is pivotal in preparing the body for either fight or flight. In the brain, noradrenergic cell bodies are found in the locus coereleus where the highest NET densities are also found. Lower densities are found in the thalamus, hypothalamus, and neocortex. In general, NET density is much lower than that of the...

Case Study Benztropine Analogues

As can be seen in Fig. 1, benztropine (3a-diphenylmethoxytropane, abbreviated herein as BZT) shares structural features with cocaine (tropane ring) and the diphenyl ether of the phenylpiperazines. A prototype of this latter Fig. 1 Chemical structures of cocaine, benztropine (BZT) and GBR 129009 Fig. 1 Chemical structures of cocaine, benztropine (BZT) and GBR 129009 class is GBR 12909, which is a selective DA uptake inhibitor that was selected for clinical evaluation as a cocaine-abuse...

Serotonin Transporters SERTs

Serotonin (5-hydroxytryptamine, 5-HT) is implicated in a number of home-ostasis functions, such as food intake, sleep, and temperature regulation, but also in regulation of mood. The serotonergic neurons project from raphe nuclei and the highest SERT densities are found in thalamus, striatum, and raphe nuclei which thus become suitable targets for measurement of SERT binding potential using PET. Disturbances in the serotonin system may lead to various mental illnesses, such as anxiety and...

Amino Acid Derived GlyT1 Inhibitors

The majority of work on glycine transporter inhibitors has focused on the discovery of selective GlyTl inhibitors, and the first such reported selective inhibitor was sarcosine 2, Fig. 4 52 . Sarcosine is an endogenous amino acid and is a competitive inhibitor of GlyTl with negligible activity against GlyT2 4,6 . It is produced naturally via the metabolism of choline, primarily thought to occur in the liver and kidney, and in turn is further metabolised by glycine-N-methyltransferase to produce...

Non Amino Acid Derived GlyT1 Inhibitors

As previously discussed, the optimisation of amino acid-based structural motifs has allowed for the identification and development of a series of potent and selective GlyT1 inhibitors. However, recent literature is suggesting a general shift away from the use of amino-acid derivatives as glycine uptake inhibitors, with over 40 patents having been published on non-sarcosine-based compounds since 2006. In addition, several candidates have entered clinical trials during this period and, whilst the...