Disease relevance of MDL 72222

• Bemesetron significantly reduced catalepsy at a dose of 1 mg/kg, whilst 10 mg/kg potentiated the phenomenon and 0.1 mg/kg was found to be without effect [1].
• MDL-72222, which had no effects on temperature when given alone, significantly attenuated m-CPBG-induced hyperthermia [2].
• All the effects of injected 5-HT on chemosensory discharge could be abolished by the combination of MDL 72222 and ketanserin (100 micrograms kg-1, i.c.). Neither MDL 72222 nor ketanserin had any significant effect upon the response of the carotid chemoreceptors to hypoxia [3].
• The effect of the neuronal 5-HT3 receptor antagonist MDL 72222 has been investigated on the reflex tachypnoeic response to pulmonary embolism in pentobarbitone-anaesthetized rabbits [4].
• MDL 72222 had no effect on the bradycardia associated with embolization; however, it significantly reduced the decrease in arterial blood pressure and converted the decrease in tidal volume seen in pulmonary embolism to an increase [4].

Psychiatry related information on MDL 72222

• Locomotor activity was unaffected by m-CPBG, but was dose-dependently reduced by MDL-72222, an effect which may have contributed to its hypophagic effects [2].
• The effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by L-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated [5].
• Citalopram and WAY-100,635 had no significant effects, RU-24969 appeared to disrupt responding, and MDL-72222 reduced premature responses and the number of short reaction times [6].
• MDL 72222 (0.1-1.0 mg/kg, s.c.) induced a delayed and dose-dependent increase of slow wave sleep [7].
• Pretreatment with MDL 72222 (0.1-0.5 mg/kg) prevented the effects of m-chlorophenylbiguanide (50 micrograms) on wakefulness and sleep [7].

High impact information on MDL 72222

• Recently, GR38032F, MDL 72222 and ICS 205-930 have been shown to have behavioural effects in rodents and primates that undoubtedly reflect an action in the central nervous system (refs 9-11 and unpublished observations), suggesting the existence of 5-HT3 receptors in the brain [8].
• Membranes from transfected cells showed high-affinity binding of the serotonin antagonists spiperone, ketanserin and mianserin, low affinity for haloperidol (a dopamine D2 receptor antagonist), 8-OH-DPAT as well as MDL-72222 and no detectable binding of [3H]serotonin [9].
• Binding of [3H]5-HT to enteric membranes is inhibited by 5-HT1P receptor agonists and antagonists but not by the 5-HT2P receptor antagonist ICS 205-930 or by MDL 72222, another compound reported to be an antagonist of 5-HT at peripheral receptors [10].
• Our results suggest that MDL 72222 attenuates MAP-induced behavioral sensitization via 5-HT(3) receptors in the caudate putamen, and that 5-HT(3) receptor antagonists like MDL 72222 have potential as novel anti-psychotic agents for the treatment of MAP dependence and psychosis [11].
• The depolarizing response was mimicked by the 5-HT2 receptor agonist (+2-)-1(2,5-dimethyoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) and blocked by 5-HT antagonists methysergide and cyproheptadine and by 5-HT2 antagonists ketanserin and spiperone; methiothepin and MDL 72222 were without effect [12].

Chemical compound and disease context of MDL 72222

• The subtype-selective serotonin 5-HT3 antagonists MDL 72222 and ICS 205-930 were tested for their ability to modify nicotine self-administration and locomotor activity in rats [13].

Biological context of MDL 72222

• Food intake in freely fed rats was unaffected by m-CPBG or MDL-72222 [2].
• In inhibition studies with cold MDL 72222 (1 mg.kg-1) as pretreatment, co-injection or displacement, no clear-cut effects on the kinetics of [11C] MDL 72222 in brain were detected in any region, including those known to be rich in 5-HT3 receptors [14].
• 4. Increased mechanoreceptor responsiveness produced by 5-HT was reduced or abolished by the 5-HT3 receptor antagonists studied (MDL 72222, ICS 205-930, or GR 38032F, in single doses of 100 micrograms kg-1, i.a.). 5. Fast excitation showed marked tachyphylaxis and was antagonized by MDL 72222, ICS 205-930 or GR 38032F [15].
• The 5-HT3 receptor antagonist, MDL 72222, dose-dependently potentiates morphine-induced immediate-early gene expression in the rat caudate putamen [16].
• Potent 5-HT3 receptor antagonists showed nanomolar affinities for [3H]ICS 205-930 binding sites with the following rank order of potency: SDZ 206-830 greater than ICS 205-930 greater than SDZ 206-792 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than SDZ 210-204 greater than MDL 72222 greater than SDZ 210-205 [17].

Anatomical context of MDL 72222

• Thus, in the neuronal cell line cytosolic Ca2+ activity is raised through enhancement of Ca2+ entry into the cells from the extracellular environment via 5-HT3 receptors (blocked by ICS 205-930, MDL 72222 and GR 38032 F) [18].
• Quipazine, MDL 72222 and ICS 205-930 were also shown to be effective antagonists of 5-HT on the vagus nerve [19].
• Apparent pA2 values were determined from individual experiments on both the nodose and superior cervical ganglia, where MDL 72222 (10(-7) M or less, for 1 hr) caused parallel or near parallel shifts of dose-response curves [20].
• In the nodose ganglion, after equilibration for 1 hr with 10(-8) or 10(-7) M MDL 72222, dose-response curves for 5-HT showed rightward, parallel shifts [20].
• The facilitations of the ventral root potentials were blocked by the serotonin1A antagonist spiroxatrine, but were unaffected by the serotonin2 antagonist ketanserin or the serotonin3 antagonist 1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,-dichlorobenzoate (MDL 72222) [21].

Associations of MDL 72222 with other chemical compounds

• 6. The relaxation responses to 5-HT were neither inhibited by antagonists selective for 5-HT1 or 5-HT2 receptors nor by the 5-HT3 receptor antagonists, ondansetron, granisetron or MDL 72222 [22].
• The effect of two potent and specific antagonists of 5HT3 receptors, ICS 205-930 and MDL 72222, on the reinforcing properties of amphetamine, morphine and nicotine was studied in rats [23].
• The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT3 antagonist, MDL 72222, failed reliably to attenuate drug key responding [24].
• The 5-HT2 antagonists ritanserin and ketanserin and the selective 5-HT3 antagonists ICS 205-930 and MDL 72222 had no effect on food intake [25].
• 5-HT-induced increases in [Ca(2+)](i) were inhibited by MDL 72222, a selective 5-HT(3) receptor antagonist, and nifedipine, an L-type calcium channel blocker, but not by ketanserin, a 5-HT(2) receptor antagonist, or thapsigargin, a specific inhibitor of endoplasmic reticulum Ca(2+)-ATPase [26].

Gene context of MDL 72222

• Alternatively, animals were pretreated with the CCK1 receptor antagonists devazepide and lorglumide or the 5-HT3 antagonist MDL-72222 before SO-SBTI administration [27].
• ICS 205-930, MDL 72222, and LY 278584 (at micromolar concentrations) reduced GABA-gated chloride currents studied in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2S GABAA receptor subunits [28].
• Attenuation of defensive analgesia in male mice by 5-HT3 receptor antagonists, ICS 205-930, MDL 72222, MDL 73147EF and MDL 72699 [29].
• The stimulation by 5-HT (less than or equal to 10(-5) M) was principally antagonized by MDL 72222 [30].
• The 5-HT3 receptor antagonists, ICS 205-930 and MDL 72222, displace 47-55% of the specific [3H]serotonin (100 nM) binding to synaptosomal membranes derived from the dorsal, but not ventral, spinal cord of rats with IC50s less than 1.0 nM [31].

Analytical, diagnostic and therapeutic context of MDL 72222

• The channel activity induced by bath perfusion of 5-HT (0.8 microM) was significantly reduced by 100 nM of the 5-HT3 receptor-specific antagonists 3-tropanyl-3,5-dichlorobenzoate (MDL 72222) or 3-tropanyl-indole-3-carboxylate (ICS 205-930) [32].
• Both MDL 72222 and MDL 73147EF produced flat dose-response curves, with significant inhibition of defensive analgesia at minimum effective doses of less than or equal to 10 and 300 micrograms/kg, respectively [29].
• Intrathecal injection of the 5-HT(2) receptor antagonist RS 102221 and the 5-HT(3) receptor antagonist MDL 72222 had no significant effects on the increased hindpaw withdrawal latencies to both noxious stimulations induced by intra-periaqueductal gray injection of morphine [33].
• Intravenous injection of the 5-HT3 antagonist MDL 72222 (1.0 mg kg-1) markedly attenuated the responses to phenylbiguanide.(ABSTRACT TRUNCATED AT 250 WORDS)[34]
• The drug MDL 72222, a selective 5-HT3 receptor antagonist, was labelled with 11C and evaluated for distribution kinetics in brain and in vivo binding to 5-HT3 receptors using cold MDL 72222 challenge and positron emission tomography (PET), in three anaesthetized baboons [14].

References