Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton: synthesis, structure, biological activity, and comparative molecular field analysis studies.

Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.

Hepatic protoporphyria is associated with a decrease in ligand binding for the mitochondrial benzodiazepine receptors in the liver.

Protoporphyrin IX (PP) and N-methylprotoporphyrin IX (N-MePP) added in vitro to liver membranes reduced dose-dependently the affinity of [3H]PK 11195 for the mitochondrial benzodiazepine receptors (MBRs), the latter being about 20 times more potent (Ki 4.5 and 0.25 microM). Preincubation of these two porphyrins with liver homogenates for 120 min at 4 degrees resulted in significant inhibition of [3H]PK 11195 binding even after repeated washings of the membranes due to the residual presence in the membranes of about 35 and 5% of PP and N-MePP, respectively. Thus, the hypothesis that an in vivo increase in the hepatic porphyrin content modifies the binding of the isoquinoline PK 11195 to the MBRs was investigated in an experimental model of protoporphyria. PP and N-MePP were allowed to accumulate in vivo through treatment with 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) (100 mg/kg i.p., once), and rats were killed 5 h after treatment when hepatic porphyrin accumulation was marked (10-fold increase), PP predominating. In the liver, treatment reduced the affinity (Kd) of [3H]PK 11195 for MBRs (from 3.56 to 15.37 nM, P < 0.01) and the maximum number of binding sites (Bmax) (55% decrease, P < 0.05); the affinity (Ki) of RO 5-4864 for [3H]PK 11195 binding sites was also reduced (from 23.9 to 72.99 nM, P < 0.05). No significant differences were found in the brain cortex. Liver and brain diazepam binding inhibitor levels and plasma corticosterone levels were unchanged. The reduction in [3H]PK 11195 binding to MBRs in the liver of DDC-treated rats thus appears to be attributable to a specific effect of the DDC-induced formation of the two protoporphyrins; this conclusion suggests that in hepatic protoporphyria processes modulated by MBRs may be altered.

Brain uptake and distribution of the potential memory enhancer CL 275,838 and its main metabolites in rats: relationship between brain concentrations and in vitro potencies on neurotransmitter mechanisms.

The kinetics, brain uptake and distribution of CL 275,838, a potential memory enhancer, and its main metabolites (II and IV) were evaluated in rats after intraperitoneal doses of 5, 10 and 20 mg/kg. Brain maximum concentrations (Cmax) of the three compounds after pharmacologically active doses were then related to the in vitro concentrations affecting some monoaminergic and amino acid receptor sites to examine the relative importance of these neurotransmitter systems in the pharmacological actions of CL 275,838. After 10 mg/kg CL 275,838, the unchanged compound rapidly entered the brain and distributed almost uniformly in various regions inside the blood-brain barrier. Its disappearance from brain and plasma was almost parallel with a comparable elimination half-life (t 1/2) of about 2 h. Metabolite II entered the brain and equilibrated with plasma more slowly than the parent compound, achieving mean Cmax (0.2 microM) within 3 h of dosing. Metabolite IV was rapidly detected in rat brain but hardly amounted to 10% (0.1 microM) of the parent compound Cmax (1 microM). There was a linear relationship between dose and plasma and brain concentrations of the three compounds up to 20 mg/kg CL 275,838. At micromolar concentrations the parent compound had affinity for serotonin (5-HT) uptake sites, 5-HT2 and dopamine (DA2) receptors. Only at much higher concentrations than those achieved in vivo after pharmacologically active doses did it increase the binding of 3H-glutamate to NMDA (N-methyl-D-aspartate) receptors. Metabolite II has a similar neurochemical profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors.

SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6- tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10(-7)-10(-6) M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and alpha 1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10(-6) and 10(-5) M. The effect of 10(-6) M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10(-6) M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (+/-)-sulpiride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice.

In previous work, we reported that chlorpromazine inhibits tumor necrosis factor (TNF) production in endotoxin lipopolysaccharide-treated mice, and protects against lipopolysaccharide toxicity. Chlorpromazine is used as an antipsychotic and has several effects on the central nervous system. It acts on different neurotransmitter receptors and has other biochemical activities some of which, like inhibition of phospholipase A2, might be responsible for the inhibitory effect on TNF production. To investigate the role of these actions in the inhibition of TNF production by chlorpromazine, we have synthesized some chlorpromazine derivatives that do not have central activities. Some of these analogs have lost their affinity for various receptors and their phospholipase A2 inhibitory activity, but still inhibit TNF production. No correlation was found between TNF inhibition and the ability to inhibit nitric oxide (NO) synthase, whereas a good correlation was evident between TNF inhibition and antioxidant activity.

Effect of some anesthetics on memory and exploration.

A light ether anesthesia in laboratory mice resulted in the complete drop of their memory retrieval to zero for more than three days after the administration. On the contrary, mice that underwent the exploration test after the light ether anesthesia performed as expected, confirming that impairment of memory does not necessarily reflect on exploratory performance. The effect of some anesthetic drugs was then studied on memory retrieval and exploratory behavior. Within this general framework, the anesthetics here studied all worsen memory retrieval, however without inducing clear and long-lasting amnesic effect comparable to that exerted by ether anesthesia. Contrarily, the classically amnesic drug scopolamine, orally administered, enhances memory retrieval and improves exploration.

Exploratory behavior and the dual activity of some psychoactive drugs. Part 5. Alcohol.

Alcohol is reported to impair acquisition and learning processes and it is considered a depressant of the brain activities impairing rapidity and consistency of some behaviors. The experiments reported here are concerned with the exploratory performances of the already described subpopulations of Albino mice under the effect of alcohols of different types.

Exploratory behavior and the dual activity of some psychoactive drugs. Part IV. Neuroleptics.

Exploration is an essential, life-preserving component of animal higher nervous functions. The experiments presented here show that exploratory behavior may differ in relation to the subject's emotional baseline, and that accordingly, it is affected differently by various neuroleptics.

Difference in learning and retention by Albino-Swiss mice. Part 5. Effect of some antidepressants.

According to the methods described earlier (1), the effect of some antidepressants on memory retention in "good" and "poor" learning mice was studied. The present study indicates that several antidepressants have different activity on memory retrieval of the two subtypes of animals, which is directly responsible for the results here reported. In general terms, the data obtained show that, in addition to the classical antidepressant activity, some derivatives may exert a behavioral disinhibition.

Exploratory behavior and the dual activity of some psychoactive drugs. Part III. Antidepressants.

Exploration is an essential, life-preserving component of animal higher nervous functions. The experiments presented here show that exploratory behavior may differ in relation to the subject's emotional baseline, and that accordingly it is affected differently by various antidepressants.

Synthesis and benzodiazepine receptors affinity of 2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinolin-1-one and 3-carbethoxy-4-phenylquinoline derivatives.

A series of 2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinolin-1-one derivatives and related compounds were tested for their ability to bind benzodiazepine receptors (BZRs). Most of the synthesized compounds showed micromolar affinity for BZR peripheral type, but not for the central one, with the exception of compound 4m which displayed an IC50 = 0.407 microM, only 2 fold higher than IC50 for chlordiazepoxide.

Synthesis and receptor binding studies of 2-functionalized 1,4-benzodiazepine derivatives as potential metaclazepam-like antianxiety agents.

The synthesis of 7-chloro-2,3-dihydro-2-(2-methoxyethyl)-1-methyl-5-phenyl- 1H-1,4-benzodiazepine (2) is described. While the metaclazepam-like compound 2 showed an affinity for benzodiazepine receptor central type (CBZRs) comparable to that of metaclazepam (1a), its intermediates bearing the exocyclic double bond resulted more active.

Synthesis and 5-HT receptors binding studies of some 3-substituted-2-(4-methyl-1-piperazinyl)-4-phenylquinolines.

The syntheses of some 3-substituted-2-(4-methyl-1-piperazinyl)-4-phenylquinolines are reported. The title compounds were tested for their potential activities on 5-HT receptor subtypes and 5-HT uptake site; compounds 4b-d showed micromolar affinity for 5-HT3 and 5-HT uptake site.

Some central effects of opioid antagonists. Part I.

This study concerned the influence of opioid antagonists: naloxone, naltrexone and diprenorphine on amphetamine hyperactivity in mice and rats, apomorphine hyperactivity in rats, amphetamine and apomorphine stereotypy in rats, and stereotyped gnawing induced by methylphenidate in mice. Naloxone, naltrexone and, in higher doses, diprenorphine attenuated the amphetamine hyperactivity in rats. In mice in the same test all antagonists at some doses produced attenuation. However they did not affect the apomorphine hyperactivity in rats. Both naloxone and naltrexone attenuated amphetamine and apomorphine stereotypy, while the effect of diprenorphine was different: it slightly attenuated the amphetamine stereotypy, but slightly potentiated the stereotypy induced by apomorphine. The influence of various antagonists on methylphenidate-induced stereotyped gnawing varied: naloxone had no effect, while naltrexone and diprenorphine showed a tendency to potentiate the response. The results suggest that naloxone and naltrexone show some actions resembling hose of antipsychotics, but of a mechanism different to that characteristic of typical neuroleptics.

Synthesis and dopamine receptor binding of 4-(2-aminoethyl)-1H-pyrazole and its N,N-dialkyl derivatives.

The agnostic activity of Quinpirole (3a) at the D2 dopamine (DA) receptor suggested that the dopaminergic pharmacophore embedded in 3a was the 4-(2-aminoethyl)-1H-pyrazole (5) moiety. On that basis we have synthesized some derivatives of 5 bearing on the amino group alkyl and alkylaryl substituents. The affinities of 5 and its derivatives for the D1 and D2 DA receptor subtypes were evaluated in rat striatum by binding assays. None of these compounds show affinity for the D1 receptor. In the D2 binding assay only the N,N-di-(2-phenylethyl) (5i) and N-n-propyl-N-[2-(3-hydroxyphenyl)ethyl] (5j) derivatives show affinities comparable to that of Quinpirole. These results do not support the postulate that the 4-(2-aminoethyl)-1H-pyrazole is a bioisostere of the catechol nucleus of DA.