Transport inhibitors

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Nimodipine, but not other DHPs, is also a potent inhibitor of nucleoside transport with actions similar to known nucleoside transport inhibitors such as dipyr-idamol. It is likely that this mechanism also contributes to the potent vasodilating properties of this DHP. 

The localization of transporter molecules on the cell surface is dynamic rather than constitutive, such that transport capacity may be adapted to neuronal activity. Obviously, the mechanisms regulating uptake are of principal importance in pharmacology just as pharmacological transport inhibitors can regulate the density of transporters. 

Therefore, dopamine transporter inhibitors exhibit less effect in the FC. There, dopamine seems to be reuptaken by the norepinephrine transporter, which dopamine actually has a higher affinity for than norepinephrine itself. 

Fig. 1. The structures of sugar-transport inhibitors, (a) Phloretin, (b) diethylstilboestrol, (c) 2-A -[4-(l-azi-2,2,2-trifluoroethyl)benzoyl]-l,3-bis-(D-mannos-4-yloxy)-2-propylamine (ATB-BMPA), (d) forskolin, (e) androsten-4-ene-3,17-dione, (0 cytochalasin B.

A. M. Hirsch, R. V. Bhuvaneswari, J. G. Torrey and T. Bisseling, Early nodulin genes are induced in alfalfa root outgrowths elicited by auxin transport inhibitors. Proc. Natl. Acad. Sci. U.S.A. 86 1244-1248 (1989). 

ANANDAMIDE TRANSPORT INHIBITORS The Hydrophobic Chain The Carboxamide/Carboxylate Group The Polar Head Group... 

Anandamide is inactivated in two steps, first by transport inside the cell and subsequently by intracellular enzymatic hydrolysis. The transport of anandamide inside the cell is a carrier-mediated activity, having been shown to be a saturable, time- and temperature-dependent process that involves some protein with high affinity and specificity for anandamide (Beltramo, 1997). This transport process, unlike that of classical neurotransmitters, is Na+-independent and driven only by the concentration gradient of anandamide (Piomelli, 1998). Although the anandamide transporter protein has not been cloned yet, its well characterized activity is known to be inhibited by specific transporter inhibitors. Reuptake of 2-AG is probably mediated by the same facilitating mechanism (Di Marzo, 1999a,b Piomelli, 1999). 

Capece, M. L., Efange, S. M. Lydic, R. (1997). Vesicular acetylcholine transport inhibitor suppresses REM sleep. Neuroreport 8, 481-4. 

Adenosine has been proposed to induce sleep by inhibiting cholinergic neurons of the BFB and the brainstem. In this respect, adenosine and the adenosine transport inhibitor NBTI decrease the discharge rate of BFB neurons during W, whereas the adenosine Ai receptor antagonist CPDX induces the opposite effects (Alam et al., 1999 Strecker et al., 2000). In addition, perfusion of adenosine into... 

Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus. Epilepsy Res. 2 (2), 65-71. 

Hoppenbrouwers, M. L. Van den Busche, G. (1987). Mioflazine, a nucleoside transport inhibitor effective as sleep promotor in humans . Abstract, International Symposium Current Trends in Slow Wave Sleep Research, Beerse, Belgium, p. 38. 

Wauquier, A., Van Belle, H., Van den Broeck, W. A. Janssen, P. A. (1987). Sleep improvement in dogs after oral administration of mioflazine, a nucleoside transport inhibitor. Psychopharmacology 91 (4), 434-9. 

Hanania, T. and Zahniser, N.R., Locomotor activity induced by noncompetitive NMDA receptor antagonists versus dopamine transporter inhibitors opposite strain differences in inbred long-sleep and short-sleep mice, Alcohol Clin. Exp. Res., 26, 431, 2002. 

Czoty, P.W., Ramanathan, C.R., Mutschler, N.H., Makriyannis, A., Bergman, J. Drug discrimination in methamphetamine-trained monkeys effects of monoamine transporter inhibitors. J. Pharmacol. Exp. Ther. 311 720, 2004. 

Sekine, T., Cha, S. H., Niwa, T., Endou, H., Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors, J. Pharmacol. Exp. Ther. 2002, 301, 797-802. 

BMS-505130 (7) is a potent and selective serotonin transporter inhibitor (SERT K< = 0.18 nM, NET K< — 4.6 gM, DAT K< — 2.1 (tM). In brain microdialysis studies, 7 demonstrated a dose-dependent increase in cortical serotonin levels. Compound 7 was also active in the mouse tail suspension model [15]. Following oral administration, peak plasma concentration of 7 was reached at 1.6 h and then declined to a concentration less than 10% of Cmax within 6 h. The short half-life of 7 might be advantageous for the treatment of PE where an acute effect to delay ejaculation followed by a relatively rapid fall in SSRI plasma concentration might be desirable. 

In brief, the rats are anesthetized, followed by an injection of 0.2 mL of the test solution into the common carotid artery. The injection solution consists of a HEPES buffered Ringer s solution (containing 141 mM NaCl, 4 mM KC1, 2.8 mM CaCl2, and 10 mM HEPES, pH 7.4) which contains both the test substrate (e.g., a [3H]-labeled compound, about 10 /xCi) and a reference compound, which is highly extracted by the tissue (e.g., 0.1 /xCi [14C]n-butanol) in the presence or absence of transport inhibitors. If a [14C]-labeled compound is used as a test substrate, [3H]H20 can be selected as a reference compound. Rats are decapitated at 15 s after injection and the retina is removed. The retina is dissolved in 2 N NaOH and subsequently neutralized with 2 N HC1. The radioactivity is measured by liquid scintillation spectrometry. The RUI value, an index of the retinal distribution characteristics of the [3H] test substrate, is estimated using the following relationship ... 

Hoffman, B.T., Kopajtic, T., Katz, J.L., and Newman, A.H. 2D QSAR Modeling and preliminary database searching for dopamine transporter inhibitors using genetic algorithm variable selection of Molconn Z descriptors./. Med. Chem. 

Oulianova N, Falk S, Berteloot A. (2001) Two-step mechanism of phlorizin binding to the SGLTl protein in the kidney. JMembr Biol 179 223-242. White JR. (2010) Apple trees to sodinm glucose co-transporter inhibitors A review of SGLT2 inhibition. Clinical Diabetes 28 5-10. 

None of these had pronounced herbicidal activity but rather PGR activity. Compound % for example, has been shown to be an auxin transport inhibitor, a property probably shared by the other members of this class also. A structure activity analysis for this group of compounds has been reported by Katekar ( ) ... 

Lock EA, Ishmael J. 1985. Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates. Toxicol AppI Pharmacol 81 32-42. 

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