Central nervous system distribution

Stewart DJ, Leavens M, Maor M, et al. Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer Res 1982 42 2474-2479. 

Hirst WD, Abrahamsen B, Blaney FE, et al. Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol Pharmacol 2003 64 1295-1308. 

TriboUet E, Duboisdauphin M, Dreifuss JJ, Barberis C, Jard S (1992) Oxytocin receptors in the central-nervous-system - distribution, development, and species-differences. Ann N Y Acad Sci 652 29-38... 

Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system Distribution, regulation and function. / Neurochem. 2005 94 1-14. 

Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

Neurotensin. This hormone has been isolated and characterized from acid—acetone extracts of bovine hypothalamus (118) on the basis of its hypotensive activity. Immunoreactive neurotensin is present in mammalian gut and is distributed throughout the central nervous system its highest concentration is in the hypothalamus and in the substantia gelatinosa of the spinal cord (119). Its overall brain distribution is not unlike that of enkephalin ( ) ... 

CGRP is widely distributed throughout the peripheral and central nervous systems and is found ia sensory neurons and ia the autonomic and enteric nervous systems. In many iastances CGRP is co-localized with other neuroregulators, eg, ACh ia motor neurons, substance P, somatostatin, vasoactive intestinal polypeptide (VIP), and galanin ia sensory neurons. It is also present ia the CNS, with ACh ia the parabigeminal nucleus and with cholecystokinin (CCK) ia the dorsal parabrachial area. CGRP functions as a neuromodulator or co-transmitter. 

Neurotensin. Neurotensia [39379-15-2] (NT),j )-Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Try-Ile-Leu-OH, is a tridecapeptide that is cleaved from the ribosomaHy synthesized precursor, proneurotensia. NT is distributed through the peripheral and central nervous systems as well as ia certain other cell types (3,67). NT is colocalized with catecholamines ia some neurons. 

TCDD is the most potent inducer of chloracne. This has been well known since the accident in Seveso, Italy, in 1976 in which large amounts of TCDD were distributed in the environment subsequent to an explosion in a factory that produced a chlorophenoxy herbicide, 2,4,5-T. TCDD is an impurity produced during the production of 2,4,5-T. The most common long-term effect of TCDD exposure was chloracne. Exposed individuals also suffered increased excretion of porphyrins, hyper-pigmentation, central nervous system effects, and liver damage and increased risk of cancer was a long-term consequence of the exposure. In addition to TCDD, polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans, and polychloronaphthalens cause chloracne as well as other effects typical of TCDD. 7i... 

Histamine is a biogenic amine that is widely distributed in the body and functions as a major mediator of inflammation and allergic reactions, as a physiological regulator of gastric acid secretion in the stomach, as a neurotransmitter in the central nervous system (CNS) and may also have a role in tissue growth and repair. 

NHE5. The distribution of this isoform is distinct, being in neuronal-rich areas of the central nervous system. Low levels have also been found in testis, spleen and skeletal muscle. Like the preceding isoforms, NHE5 is found in the plasma membrane and is internalised by clathrin-associated endocytosis into recycling endosomes. The normal role of NHE5 is unknown but its malfunction is speculated to contribute to the development of neurodegenerative disease. 

Neuromedin U is a neuropeptide which is widely distributed in the gut and central nervous system. Peripheral activities of neuromedin U include stimulation of smooth muscle, increase in blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. The actions of neuromedin U are mediated by G-protein coupled receptors (NMU1, NMU2) which are coupled tO Gq/11. 

Several splice variants of MOP (formerly MOR-1) have been cloned (MOP-1A to MOR-1X). The B, C, andD variants differ in their amino acid sequence at the C-terminal end [4]. These receptor valiants differ in their distribution in the central nervous system and in the rate of internalization and desensitization upon... 

TK NKxr displays a broad distribution in both peripheral tissues and in the central nervous system (CNS). In both CNS and enteric neurons, NKxr stimulation increase their excitability, whereas in trigeminal ganglion neurons SP has no intrinsic electrophysio-logical effects but is capable to enhance the amplitude of the inward current induced by the stimulation of serotonin 5-HT3 recqrtors. This enhancement dqjends on the activation of PKC via the stimulation of NKX recqrtors. This is an interesting case of receptor cross talk. Other functions of NKxr have been also highlighted. 

Other anesthetics susceptible to abuse, such as ether and chloroform, have received far less attention, because they are considered to be less commonly abused substances. Nonetheless, when inhaled, ether and chloroform are also rapidly absorbed and distributed in the central nervous system (CNS), inducing a rapid euphoria. Ether and chloroform inhalation is facilitated by the fact that they have a low boiling point (i.e., approximately 34°C) (Delteil et al. 1974). 

The distribution of endosulfan and endosulfan sulfate was evaluated in the brains of cats given a single intravenous injection of 3 mg/kg endosulfan (Khanna et al. 1979). Peak concentrations of endosulfan in the brain were found at the earliest time point examined (15 minutes after administration) and then decreased. When tissue levels were expressed per gram of tissue, little differential was observed in distribution among the brain areas studied. However, if endosulfan levels were expressed per gram of tissue lipid, higher initial levels were observed in the cerebral cortex and cerebellum than in the spinal cord and brainstem. Loss of endosulfan was most rapid from those areas low in Upid. Endosulfan sulfate levels peaked in the brain at 1 hour postadministration. In contrast, endosulfan sulfate levels in liver peaked within 15 minutes postadministration. The time course of neurotoxic effects observed in the animals in this study corresponded most closely with endosulfan levels in the central nervous system tissues examined. 

Neurotransmitter receptors have evolved as one of the key components in the ability of the central nervous system to coordinate the behaviour of the whole animal, to process and respond to sensory input, and to adapt to change in the environment. These same receptors are therefore ideal targets for drug action because of their central role in the activity of the nervous system. A rational approach to the development of new therapeutic strategies involving the action of drugs at receptors in the nervous system is based on knowledge of receptor structure, distribution and function. 

Figure 9.1 The distribution of 5-HT neurons in the brain. The cell bodies are clustered in nuclei (B1-B7) in the pons/upper medullary regions of the brainstem. The rostral cluster ( superior group ) project mainly to forebrain areas while the caudal ( inferior ) group projects mainly to the medulla and spinal cord. Collectively, these neurons innervate most regions of the central nervous system...

Aqueous solubility is not usually considered a priori as a problem in the drug discovery of acidic compounds. More important issues are (i) the high serum albumin binding of stronger acids, (ii) the very low or nonexistent central nervous system penetration of stronger acids, (iii) the low volumes of distribution of acids limiting these mostly to plasma compartment targets, (iv) the possibility of formation of... 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Kelder et al. [19] have shown that PSA can be used to model oral absorption and brain penetration of drugs that are transported by the transcellular route. A good correlation was found between brain penetration and PSA (n=45, r=0.917). From analyzing a set of 2366 central nervous system (CNS) and non-CNS oral drugs that have reached at least phase 11 clinical trials it was concluded that orally active drugs that are transported passively by the transcellular route should have PSA< 120 Al In addition, different PSA distributions were found for CNS and non-CNS drugs. 

Fuxe, K. Evidence for the existence of monoamine neurons in the central nervous system. IV. Distribution of monoamine nerve terminal in the central nervous system. Acta Physiol Scand (Suppl 247) 64 39-85, 1965. 

Steinbusch, H.W.M. Distribution of serotonin-immunoreactivity in the central nervous system of the rat—Cell bodies and terminals. 

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