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Gastric H+, K(+)-ATPase plays a pivotal role in the final step of gastric acid secretion. Over 80 flavonoids, including flavones, flavanones, isoflavones and anthocyanidins were examined for their in vitro effect on gastric H+, K(+)-ATPase and some were found to be inhibitors of this enzyme. Kinetic studies showed that the inhibition of H+, K(+)-ATPase by flavonoids was competitive with respect to ATP, and non-competitive with respect to K+. Structure-activity analysis revealed the following: (1) The inhibitory potency of flavonoids depends on the number of hydroxyl groups up to four per molecule and that above this, no marked enhancement is seen; (2) The hydroxylation pattern is an important determinant of inhibitory potency. Two adjacent hydroxyl groups (catechol-type), three adjacent hydroxyl groups (pyrogallol-type) or hydroxyl groups at C-3, C-5 and C-7 are a minimum requirement for high potency inhibition; (3) Protection of the hydroxyl group(s) by glycosylation or methylation decreases potency; (4) Saturation of the C-2-C-3 double bond results in a decrease in potency; and (5) A ketone at C-4 is not essential for inhibition.

1 The atypical antipsychotic pro®le of (R)-(+)-2-amino-4-(4-¯uorophenyl)-5-[1-[4-(4-¯uorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D 4 and 5-hydroxytryptamine (5-HT) 2A receptor antagonist, was examined in rats. 2 Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED 50 3.7 mg kg 71 ), haloperidol (ED 50 0.1 mg kg 71 ) and chlorpromazine (ED 50 0.9 mg kg 71 ), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg 71 , did not exceed 50%. 3 Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg 71 , i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED 50 0.4 mg kg 71 , i.p., and 0.3 mg kg 71 , p.o., respectively), clozapine (ED 50 0.3 mg kg 71 , i.p. and 0.8 mg kg 71 , p.o., respectively), haloperidol (ED 50 0.02 mg kg 71 , i.p. and 0.1 mg kg 71 , p.o., respectively), chlorpromazine (ED 50 0.3 mg kg 71 , i.p. and 3.3 mg kg 71 , p.o., respectively). In contrast, the MAP (3 mg kg 71 , i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not a ected by NRA0045 or clozapine, at the highest dose given (30 mg kg 71 , i.p.). Haloperidol (ED 50 0.3 mg kg 71 , i.p.) and chlorpromazine (ED 50 4.8 mg kg 71 , i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/ mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4 Extracellular single-unit recording studies demonstrated that MAP (1 mg kg 71 , i.v.) decreased the ®ring rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 0.1 mg kg 71 , i.v.), whereas the inhibitory e ects of MAP on A9 dopamine neurones were not a ected by NRA0045, in doses up to 1 mg kg 71 (i.v.). Clozapine completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 1.9 mg kg 71 , i.v.) and on A9 dopamine neurones (ED 50 2.5 mg kg 71 , i.v.). Haloperidol completely reversed the inhibitory e ects of MAP on A10 (ED 50 0.03 mg kg 71 , i.v.) and on A9 dopamine neurones (0.02 mg kg 71 , i.v.). NRA0045, like clozapine, was more potent in reversing the e ects of MAP on A10 than A9 dopamine neurones. 5 Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg 71 , s.c.) was reversed signi®cantly by NRA0045 (3 mg kg 71 , i.p.), clozapine (3 mg kg 71 , i.p.) and haloperidol (0.3 mg kg 71 , i.p.). 6 Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03 ± 0.3 mg kg 71 , i.p.) and clozapine (0.1 ± 1 mg kg 71 , i.p.) signi®cantly and dose-dependently shortened the PCP(1.25 mg kg 71 , i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (...