Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamides was synthesized, starting from the 2,6-dimethoxybenzoic acids, by boron tribromide demethylation of the corresponding 3,5-disubstituted 2,6-dimethoxybenzamides and separation of the two positional isomers. The correct structure assignments were based on selective decoupling studies on their 13C NMR spectra. The salicylamide derivatives were tested for antidopamine activity in vivo by their ability to inhibit the apomorphine syndrome in the rat and in vitro by their ability to displace [3H]spiperone from striatal preparations of the rat brain. The activity seems to reside exclusively in the S enantiomer. Several compounds were considerably more potent than haloperidol, particularly those having an ethyl group in the 3-position and a halogen atom in the 5-position of the aromatic ring. The corresponding 5-alkyl-3-halogen-substituted compounds were much less active. A low acute toxicity was found for the most potent compounds. Some of the salicylamides displayed a 10-20-fold separation between the dose which blocks apomorphine-induced hyperactivity and that which blocks apomorphine-induced stereotypy. One compound, S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide (raclopride, FLA 870) (13) had a stereotypy--hyperactivity separation more than twice that of sulpiride while being 100 times more potent in blocking the apomorphine effects. On this basis, 13 was selected for clinical trials against schizophrenia.
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PMID:Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides. 394 14

The influence of three selective monoamine receptor antagonists on spontaneous locomotion and on the hyperlocomotion induced by the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine) was investigated. The selective and potent 5-hydroxytryptamine (5-HT)2A receptor antagonist R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol (MDL100,907; M100907) displayed a clear-cut selectivity for reduction of MK-801-induced as compared to spontaneous locomotion, in that the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) blocked and even totally abolished by the highest dose, while the latter was only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. The selective dopamine D1 receptor antagonist (-)-[4aR, 10 aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl- benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a slight preference for the latter; spontaneous locomotion was dose-dependently diminished to approx. 10% of controls (at 8 mg/kg i.p.). The dopamine D2 receptor antagonist raclopride ([(-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.33, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomotion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several combinations of different doses of the 5-HT2A receptor antagonist and the dopamine D1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M100907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that the 5-HT2A receptor antagonist M100907 will have efficacy in treating this condition. The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine receptor antagonists, will be less prone to induce psychomotor side-effects. Ongoing clinical studies will hopefully give the answers in the near future.
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PMID:MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride. 936 62