Disease relevance of Alaproclate

• Alaproclate inhibits potassium currents and thereby enhances muscarinic stimulation in N1E-115 neuroblastoma cells [1].
• A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency [2].

Psychiatry related information on Alaproclate

• Elevating 5-HT in the LHAA by microinjecting alaproclate inhibited copulation by increasing the latency to mount, intromit, and ejaculate [3].
• Alaproclate: a pharmacokinetic and biochemical study in patients with dementia of Alzheimer type [4].
• A double-blind comparison of alaproclate and placebo in the treatment of patients with senile dementia [5].
• Alaproclate also reduced REM sleep [6].
• The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied [7].

High impact information on Alaproclate

• From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties [8].
• At depolarized potentials the alaproclate-induced block of the NMDA receptor current was strongly reduced, a result opposite to that seen with the voltage-activated K+ currents, suggesting that the K+ channel block may occur at a superficial internal site, whereas the NMDA receptor block occurs at a deep external site [9].
• (+)-Alaproclate was a more potent blocker of K+ currents than (-)-alaproclate, whereas a reversed stereoselectivity was observed for NMDA receptor current, supporting the view that alaproclate block of the two channel types occurs at structurally distinct binding sites [9].
• Alaproclate produced a concentration-dependent block of the sustained voltage-dependent K+ current activated by depolarization from -60 to +40 mV (IC50, 6.9 microM) [9].
• At similar concentrations alaproclate also blocked the sustained voltage-dependent K+ current in fibroblast cells transformed to stably express Kv1.2 K+ channels [9].

Chemical compound and disease context of Alaproclate

• Both zimeldine and alaproclate increased REM latency and reduced REM sleep in both species with somewhat more pronounced effects in cats than in rats [10].

Biological context of Alaproclate

• Alaproclate, a nontricyclic 5-HT uptake inhibitor, when injected 30 min prior to the administration of the cholinergic agonist, produced a dose-dependent enhancement of tremor and salivation in both rats and mice [11].
• Plasma protein binding for alaproclate was 82 +/- 1% [4].
• Alaproclate, zimelidine, PCA and desipramine produced hypoalgesia in the hot-plate but not in the tail-flick test [12].
• Alaproclate increased the probability of firing to an orthodromic input, increased the membrane resistance and prolonged the action potential [13].
• Correlations between in vitro dissolution rate and bioavailability of alaproclate tablets [14].

Anatomical context of Alaproclate

• Sertraline was a fully competitive inhibitor of high-affinity [3H]imipramine binding to platelet membranes with a Ki value of 1.3 nM, as was alaproclate and 5-HT with Ki values of 170 and 800 nM respectively [15].
• The indoleamines were measured in the anterior hypothalamus (AH), posterior hypothalamus (PH) and raphe nuclei 30 min after the i.v. injection of either alaproclate (30 mg/kg) or zimelidine (20 mg/kg) [16].
• Plasma levels of prolactin, growth hormone, luteinizing hormone, follicle stimulating hormone, and thyroid stimulating hormone remained unchanged after zimelidine and alaproclate, and the levels were comparable to those after placebo [17].
• Some other studies have reported down-regulatory effects of alaproclate and amiflamine on 5-HT2 binding sites in certain regions of the rat forebrain, but no such effects could be detected in the present study [18].
• Alaproclate increases the excitability of hippocampal CA1 pyramidal cells and blocks the slow after-hyperpolarization [13].

Associations of Alaproclate with other chemical compounds

• The other selective drug, citalopram, had a stronger effect than alaproclate in the substance P test, but in the formalin test, both drugs were approximately equally effective [19].
• Non-reversal of scopolamine- or age-related EEG changes by ondansetron, methysergide or alaproclate [20].
• The scopolamine (0.8 mg/kg)-induced EEG amplitude increase reversing potency of a subthreshold dose of the muscarinic agonist pilocarpine (2 mg/kg) was not potentiated by ondansetron, methysergide or alaproclate [20].
• Selective 5-hydroxytryptamine (5-HT) uptake inhibitors such as citalopram, alaproclate, and zimeldine showed little effect [21].
• Thus, the potentiation by alaproclate of tremor and salivation induced by the muscarinic agonist oxotremorine in-vivo reported previously is not seen when muscarinic function is measured in-vitro using carbachol-stimulated PI breakdown [22].

Gene context of Alaproclate

• This suggests that alaproclate acutely increases the responsiveness of postsynaptic muscarinic and alpha 1 adrenoceptors [23].
• In the frontal cortex, in which separate monoaminergic and tachykinin-containing neurones interact, treatment with imipramine reduced the levels of SP-LI and NKA/NKB-LI, while treatment with alaproclate had the opposite effect [24].
• By contrast, the peak of the prolactin surge in model 2 was significantly prolonged by alaproclate [25].
• In the cingulate cortex, the tissue levels of substance P and cholecystokinin were increased (19-32%) after subcutaneous (s.c.) treatment with alaproclate, compared to controls [26].
• Pretreatment with the 5-HT receptor antagonist metitepine completely blocked the enhancement of oxotremorine-induced tremor caused by alaproclate [27].

Analytical, diagnostic and therapeutic context of Alaproclate

• The hot-plate response temperatures were slightly lowered after chronic zimelidine treatment but not after treatment with alaproclate or chlorimipramine [28].
• The inhibitory response was rapidly reversed if alaproclate was removed by perfusion [29].
• The results suggest that alaproclate, which has previously been in clinical trials for depressive illness, acts as a reversible noncompetitive antagonist of the NMDA receptor [29].
• In microdialysis experiments, a s.c. injection of either saline (2 ml/kg), alaproclate (20 mumol/kg) or morphine (3 mg/kg) was found to slowly increase the substance P release in the periaqueductal grey [26].
• Alaproclate significantly enhanced morphine analgesia in the hot-plate test but did not affect morphine analgesia in the tail-flick test [12].

References