Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED50 greater than 5.0 mg/kg i.p.); production of emesis in beagles (minimum effective dose = 81 micrograms/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses less than or equal to 50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for [3H]-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED50 value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the gamma-butyrolactone-induced increase in striatal dopa levels (ED50 = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+/-)-3-PPP.
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PMID:Dopamine agonist activity of EMD 23,448. 403 93

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers. 613 38

Neuroleptics such as thioxanthenes (cis(Z)-flupentixol and cis(Z)-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiazepines.
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PMID:Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics. 614 29

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.
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PMID:Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptors agonist with greater autoreceptor selectivity than 3-PPP enantiomers. 614 47

The putative dopamine (DA) autoreceptor agonists, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and 6, 7-dihydroxy-2-dimethylaminotetralin (TL-99) were compared with apomorphine in a series of tests indicative of DA receptor activation. All three agents displaced [3H] apomorphine and [3H] spiroperidol from DA recognition sites in rat brain and caused contralateral turning in the 6-hydroxydopamine lesioned rat. Apomorphine and TL-99 were generally more potent than 3-PPP. All three agents were also active at the DA autoreceptor that controls the synthesis of dopamine as indicated in vivo using the gamma-butyrolactone (GBL) procedure and in vitro using a synaptosomal preparation. In addition, all agents produced emesis in beagles. clear differences in the drugs' actions were observed in other test procedures. In the rat, apomorphine was the only compound which caused stereotypy or rotation following a reversible KCI-induced lesion of the striatum. Conversely, TL-99 and 3-PPP lacked activity in these procedures. Presumably, activity in these two tests indicates postsynaptic DA receptor activation. Each of the putative autoreceptor agonists produced a monotonic dose-related decrease in the mouse locomotor activity as opposed to the biphasic effect exerted by apomorphine. This action on the mouse locomotor activity, coupled with the results for the GBL test, provides an index of autoreceptor activation. In contrast to 3-PPP, both apomorphine and TL-99 increased locomotor activity in animals pretreated with reserpine and alpha-methyl-p-tyrosine and caused rotation in unilaterally caudectomized mice. In these test procedures thought to reflect activity at the postsynaptic DA receptor, TL-99 differed in its action from 3-PPP in a manner which suggests 3-PPP may be a more selective DA autoreceptor agonist.
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PMID:Pharmacological profiles of the putative dopamine autoreceptor agonists 3-PPP and TL-99. 731 20

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.
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PMID:Effects of several partial dopamine D2 receptor agonists in Cebus apella monkeys previously treated with haloperidol. 810 65