Disease relevance of WB 4101

• Automatic arrhythmias induced by alpha 1-adrenergic stimulation during simulated ischemia may be attributed to a specific alpha 1-adrenergic receptor subtype that is blocked by WB 4101 [1].
• Intrathecal injection of the alpha2-adrenoceptor antagonist yohimbine did not alter the hyperalgesic effect produced by the 7.5 nmol dose of morphine, but the alpha1 antagonist WB4101 reversed the hyperalgesia and produced antinociception that lasted for nearly 30 min [2].
• Evoked mydriasis was significantly antagonized by both WB-4101 and 5-methylurapidil but not by BMY-7378 [3].
• Furthermore, subtype specific antagonism of alpha1A-adrenoceptors by WB 4101 clearly reduced the occurrence of ventricular fibrillation in a concentration-dependent manner (0.01-1 micromol/l) from 66% to 17% [4].
• In conclusion, evidence is presented of novel, direct protective effects of prazosin and WB 4101 against tetanic contracture following modified Na+ channel function and Ca2+ loading provoked by veratrine [5].

Psychiatry related information on WB 4101

• In contrast, either prazosin or WB4101 partially reversed the increase in the tail-flick response latency produced by morphine [6].

High impact information on WB 4101

• We have quantified relative potencies of tricyclic antidepressants in competing for the binding of 3H-labeled WB-4101 to alpha-noradrenergic receptor sites in rat brain membranes [7].
• In conclusion, the increase in abnormal automaticity in ischemic Purkinje fibers depends on a WB 4101-sensitive alpha 1-adrenergic receptor subtype whose actions are transduced by a PTX-sensitive 41-kd G protein and are not blocked by ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)[8]
• In contrast, WB 4101 selectively antagonized the NE-induced increase in automaticity in both age groups [9].
• In COS-7 cells transfected with cDNAs encoding the three rat alpha 1-ARs, WB-4101 and benoxathian had similar binding affinities for the alpha 1a/d-AR and the alpha 1c-AR and 10-fold lower affinities for the alpha 1b-AR [10].
• WB 4101 was 1000-fold more potent in inhibiting the [3H]InsP response in renal cells than hepatocytes; however, some of this difference was due to rapid metabolism of WB 4101 by hepatocytes [11].

Chemical compound and disease context of WB 4101

• These results suggest the alpha1-adrenoceptor subtype blocked by chloroethylclonidine, but not that blocked by WB4101, is capable of increasing the incidence of lethal arrhythmias that occur at rapid atrial rates during ischemia [12].
• These results suggest that NAN-190 is a pure antagonist of 8-OH-DPAT-induced hypothermia in rats and that BMY 7378 and WB 4101 are, respectively, a partial agonist and an agonist in this test.(ABSTRACT TRUNCATED AT 250 WORDS)[13]
• Tetrodotoxin (TTX), prazosin, WB 4101 and R 56865 (0.1-10 microM) prevented tetanic contracture elicited by veratrine (100 micrograms/ml) at concentrations which were significantly lower than those which decreased active tension development [5].
• We tested whether alpha 1A-AR stimulation by endogenous catecholamines, released during ischaemia, could modulate reperfusion arrhythmias, using as pharmacological tools the selective alpha 1A-AR antagonists abanoquil (UK52046) and WB4101 [14].

Biological context of WB 4101

• The proportions of binding sites inactivated by 10 microM CEC under hypotonic conditions were quantitatively similar to and correlated significantly (p less than 0.01) with the proportion having a low affinity for WB 4101 [15].
• Competitive binding studies with [3H]prazosin and compounds [5-methylurapidil, (+)-niguldipine, WB4101, and oxymetazoline] that distinguish high affinity (alpha 1a) and low affinity (alpha 1b) sites indicated that rat renal cortical membranes contain about 50% of each class of site [16].
• Norepinephrine stimulated [3H]inositol monophosphate production severalfold; this was blocked by alpha 1-adrenergic antagonists, including prazosin, WB 4101, and phenoxybenzamine, but by neither an alpha 2- nor a beta-adrenergic antagonist, confirming that an alpha 1-adrenoceptor is involved in the regulation of phosphatidylinositol hydrolysis [17].
• Structure-activity relationships for prazosin and WB 4101 analogues as alpha 1-adrenoreceptor antagonists [18].
• The alpha-1 antagonist WB-4101 (dimethyloxyphenoxy-ethylamino-methyl benzo-1,4-dioxan) was the most potent inhibitor of PHE in lesioned rats with an IC50 of 125 nM, 110 times lower than that of prazosin (14 microM); yohimbine and propranolol, respectively, alpha-2 and beta-antagonists caused inhibition only at very high concentrations [19].

Anatomical context of WB 4101

• Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [3H] WB4101 binding in cerebral cortex [20].
• Pretreatment of hippocampus and vas deferens with CEC caused a loss of all low affinity WB 4101-binding sites, leaving only high affinity sites [15].
• After correction for metabolism, WB 4101 was still 11-fold more potent in inhibiting norepinephrine-stimulated [3H]InsP formation in hepatocytes (alpha 1b) than in CEC-pretreated renal cells (alpha 1a) [11].
• WB4101 (1)-related compounds 5-10 were synthesized, and their biological profile at alpha(1)-adrenoreceptor (AR) subtypes and 5-HT(1A) serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors [21].
• Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl- 1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively [22].

Associations of WB 4101 with other chemical compounds

• Phentolamine and WB 4101 were significantly more potent in inhibiting specific 125IBE 2254 binding in hippocampus than in cerebral cortex [23].
• These results suggest that: 1) the CEC-sensitive and -insensitive 125IBE 2254-binding sites are equivalent to those with a low and high affinity for WB 4101, respectively, and 2) the CEC-sensitive binding sites with a low affinity for WB 4101 are the alpha 1-adrenergic receptors linked to inositol phospholipid hydrolysis [15].
• alpha 1-Adrenergic receptor subtypes were differentiated by their affinities for the competitive antagonist WB 4101 and their sensitivities to inactivation by chlorethylclonidine (CEC) in eight rat brain regions [24].
• The alpha(1A)-adrenergic receptor antagonist WB-4101 reduced PE-stimulated force by 70% and abolished PE-induced ERK phosphorylation [25].
• In this study, the effects of nine alpha-1 adrenoceptor antagonists [prazosin, WB 4101 (WB), chloroethylclonidine (CEC), 5-methylurapidil (5-MU), BMY 7378 (BMY), MDL 73005EF (MDL73), MDL 72832 (MDL72), RS 17053 (RS) and SK&F 105854 (SKF)] were studied on contractile responses to phenylephrine (PE) of the endothelium-denuded dog aorta in vitro [26].

Gene context of WB 4101

• The nonselective antagonists rauwolscine, yohimbine, WY 26703, phentolamine and corynanthine, as well as the receptor antagonists with alpha-2A selectivity like WB 4101, idazoxan and tolazoline, dose-dependently antagonized both the glycemic and the insulin responses to UK 14.304 [27].
• The low-affinity constants for WB4101 (31-51 nM) were consistent with those for the alpha 1b adrenoceptor subtype, and this binding site decreased with age [28].
• The high-affinity constant for WB4101 (1.4 nM) in 1-month-old aorta was consistent with that for alpha 1d adrenoceptor subtype, whereas the high-affinity constants (0.03 nM) in 6- and 24-month-old aortas were consistent with those for the alpha 1a adrenoceptor subtype [28].
• 4. The affinity data obtained with benoxathian, imiloxan and WB 4101 indicated the presence of an alpha 2B-adrenoceptor in rat submaxillary gland [29].
• In contrast, WB 4101 an alpha 1A-adrenoceptor-selective ligand, displaced preferentially [125I]BE 2254 binding in the hilus and the CA3 region [30].

Analytical, diagnostic and therapeutic context of WB 4101

• In addition, intraperitoneal injection of WB4101 displaces, only weakly, [3H]prazosin binding in layer III of the cerebral cortex (-18%) while it decreases by 50% [3H]prazosin binding in the more superficial cortical layers [31].
• Analgesia produced by LC stimulation was attenuated by naloxone, a morphine antagonist, cyproheptidine, a serotonin antagonist, and WB-4101, an alpha-adrenergic antagonist [32].
• Injection of the selective alpha1-adrenoceptor antagonists prazosin or WB4101 potentiated the increase in the foot-withdrawal response latency produced by microinjection of morphine in the ventrolateral periaqueductal gray [6].
• The resulting profile showed a descending order of antagonist efficacy for yohimbine, prazosin, and WB4101 for the cold-floor ambulation test and for the paw-pinch test of the affected paw [33].
• Capillary electrophoresis (CE) and chiral stationary phase (CSP) HPLC methods were investigated for the determination of enantiomeric purity of alpha1-adrenoreceptor antagonists related to WB 4101 [34].

References