The effects of 20 tricyclic and 12 chemically unrelated 'atypical' antidepressant drugs on the noradrenaline (NA) receptor coupled adenylate cyclase system were investigated in slices of the rat cerebral cortex. While no changes occurred after a single dose, 14 tricyclic compounds down-regulated the receptor system when administered for 9 days. Six tricyclic antidepressants (trimipramine, butriptyline, noxiptyline, doxepine, dosulepine, propizepine) failed to desensitize the NA sensitive adenylate cyclase although some were potent inhibitors of the neuronal uptake of NA. Using the two optically active enantiomers of oxaprotiline inhibition of NA uptake was observed with the (+)-enantiomer while the (?)-enantiomer had only weak inhibitory potency. However, in contrast to published data, both enantiomers and the racemate administered at 30 mg/kg for 9 days did down-regulate the NA receptor coupled adenylate cyclase. Therefore, the experiments were repeated with Sprague-Dawley rats from a different supplier. Now, data published earlier were reproducible, only the racemate and the (+)-enantiomer of oxaprotiline being significantly active on the desensitization of the NA sensitive adenylate cyclase. Using F-344, Long Evans and Wistar rats significant differences were found in the response of the adrenoceptor coupled adenylate cyclase to a 9 day treatment with 30 mg/kg imipramine. Although some of the atypical antidepressants are potent inhibitors of the biogenic amine uptake systems none of these compounds lead to statistically significant changes of the NA stimulated cAMP formation after a 9-day treatment period. Only with the NA uptake inhibitor tandamine and with the serotonin uptake inhibitors zimelidine and fluoxetine a trend toward adrenergic down-regulation was recognized. Using enantiomers of mianserin only the (?)-isomer which is a poor NA uptake inhibitor, was slightly active. It thus appears that the therapeutic action of antidepressant drugs cannot generally be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system. Variabilities in pharmacokinetics and in NA sensitivity of the cAMP generating system in various rat strains and possibly in different animal species may be important factors determining whether ?-receptor down-regulation will occur during chronic treatment with antidepressant drugs.

01 Apr 1977·Life SciencesQ3 · MEDICINE

Effects of tandamine and pirandamine, selective blockers of biogenic amine uptake mechanisms, on gastric acid secretion and ulcer formation in the rat

Q3 · MEDICINE

Article

Author: K. Seethaler ; W. Lippmann

Tandamine-HCl (I) [58167-78-5] and pirandamine-HCl (II) [42408-78-6] and various structurally-related compounds were examined for their effects on gastric acid secretion and ulcer formation in the rat.I and its structurally-related compounds, but not II or its structurally-related compound, given i.p., inhibited gastric acid secretion and were similar in activity to imipramine.Like imipramine, I was effective when given perorally.None of the compounds examined, administered i.p., were effective in reducing the ulcer formation in 19 h pylorus-ligated animals, while imipramine was effective.I like imipramine, inhibited ulcer formation in 10 h pylorus-ligated animals and in 19 h pylorus-ligated animals when given in divided doses.I and its structurally-related compounds, but not II or its structurally-related compound, given s.c., prevented reserpine-induced gastric ulceration; imipramine was also effective.I and imipramine, administered i.p., prevented cold-restraint gastric ulceration.The compounds which block the norepinephrine [51-41-2], or in addition the serotonin [50-67-9], uptake mechanism, but not those which block only the serotonin uptake mechanism, inhibited the gastric acid secretion and reserpine-induced ulceration.Thus, these latter activities appear to be correlated with the inhibition of the norepinephrine, rather than serotonin, uptake mechanism.

01 Aug 1976·Pharmacological Research Communications

Pirandamine, A relatively selective 5-hydroxytryptamine uptake inhibitor

Article

Author: Thomas A. Pugsley ; Wilbur Lippmann

The effects of pirandamine (I) [42408-78-6], an indeno[2,1-c]pyran, on 5-hydroxytryptamine (5-HT) [50-67-9] and norepinephrine-HCl (NE) [55-27-6] uptake mechansims were determined in mice and rats and compared to those of various tricyclic antidepressants.Structure-activity relations for this series were also determinedPirandamine potentiated the behavioral effects of dl-5-hydroxytryptophan [56-69-9] in mice, the order of activity being I ≡ chlorimipramine-HCl [17321-77-6] ≡ amitriptyline-HCl [549-18-8] > imipramine-HCl [113-52-0] > desimipramine-HCl [58-28-6].Like chlorimipramine, I blocked in vovo the 5-HT uptake in rat brain.In vitro, I was 2 times as potent as desimipramine, 2-3 times less potent than imipramine and amitriptyline and 14 times less than chlorimipramine in blocking 3H-5-HT uptake into cortical synaptosomes of rat brain.I was relatively ineffective in blocking NE uptake (ED50 > 40 mg/kg, i.p.) and guanethidine-induced NE depletion in mouse heart; desimipramine, imipramine, amitriptyline and chlorimipramine exhibited ED50's of 1.0, 5.5, 7.2, and 11.0 mg/kg, i.p., resp., for the former activity.I, in contrast to desimipramine and imipramine, did not prevent reserpine-induced hypothermia.The (-)-enantiomer [60218-35-1] of I retained the activity of the racemate; the (+)-enantiomer [60218-36-2] was much less effective.Due to its relative specificity of blockade of the 5-HT uptake mechanism in vivo, I should prove to be a useful tool in elucidating 5-HT related mechanisms and functions as well as to be a potentially useful therapeutic agent for mental depression in humans.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder	Preclinical	Canada	Wyeth-Ayerst Research	05 May 1976

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