Quinolinoneacetic acid derivatives as novel glutathione S-transferase P1-1 inhibitors: insights into the interaction modes by molecular modeling

Glutathione S-transferase P1-1 (GSTP1-1, EC 2.5.1.18) is generally conceived to be an important player in the acquired resistance of tumor to anticancer agents, thus a series of quinolinoneacetic acid derivatives were synthesized and their inhibitory effects on GSTP-1 were tested in this study. Interestingly, it was found that some compounds showed remarkable inhibitory effect on GSTP-1 activity. Furthermore, molecular docking study was conducted to provide the binding modes of quinolinoneacetic acid derivatives on GSTP1-1 activity. In summary, we present the discovery of a series of quinolinoneacetic acid compounds as inhibitors of GSTP1-1 and their interaction modes toward GSTP1-1 binding site.     

Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues

A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the cGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition.     

Synthesis, stereochemistry, and biological activity of the 1-(1-phenyl-2-methylcyclohexyl)piperidines and the 1-(1-phenyl-4-methylcyclohexyl)piperidines. Absolute configuration of the potent trans-(-)-1-(1-phenyl-2-methylcyclohexyl)piperidine

The (-)- and (+)-isomers of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines have been synthesized and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines were prepared, and their in vitro [displacement of [3H]TCP (1-[1-(2-thienylcyclohexyl)]piperidine) from the PCP (1-(1-phenylcyclohexyl)piperidine) binding site] and in vivo (rotarod assay) activities determined. The 1-(1-phenyl-2-methylcyclohexyl)piperidine isomers were resolved by classical crystallization procedures, through the diastereomeric salts obtained with d- and l-10-camphorsulfonic acid. The relative stereochemistry of the cis- and trans-Ph/Me 1-(1-phenyl-2-methylcyclohexyl)piperidines and the achiral cis- and trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidines was established by using 13C and 1H NMR. Both (-)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((-)-2) and (+)-trans-1-(1-phenyl-2-methylcyclohexyl)piperidine ((+)-2) were examined by single-crystal X-ray analysis, and the absolute configuration of (-)-2 was determined to be 1S,2R. The (-)-2 was found to be about five times more potent than PCP in vitro and twice as potent in vivo. It is the most potent of all of the simple methyl-substituted cyclohexyl PCP isomers and is among the most potent PCP-like compounds which have been synthesized. It was nine times more potent in vitro and four times more potent in vivo than (+)-2. The racemic cis-1-(1-phenyl-2-methylcyclohexyl)piperidine (3), and its enantiomers ((+)-3 and (-)-3), were essentially inactive in vitro and in vivo. The cis-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (18) was more potent than trans-Ph/Me 1-(1-phenyl-4-methylcyclohexyl)piperidine (17), but considerably less potent than (-)-2. The enantioselectivity observed at the PCP binding site for (-)-2 could indicate that this site can discriminate between enantiotopic edges of the achiral PCP (choosing the pro-1-S edge), as does the mu-opioid receptor in the prodine series of opioids. Benzimidoyl or benzoyl group replacement of the phenyl ring in the 1-(1-phenyl-2-methylcyclohexyl)piperidine series gave compounds which showed little in vitro and in vivo activity.     

2-(Hetero(aryl)methylene)hydrazine-1-carbothioamides as Potent Urease Inhibitors

A small series of 2-(hetero(aryl)methylene) hydrazine-1-carbothioamides including two aryl derivatives was synthesized and tested for their inhibitory activity against urease. Compound (E)-2-(Furan-2-ylmethylene) hydrazine-1-carbothioamide (3f) , having a furan ring, was the most potent inhibitor of urease with an IC₅₀ value of 0.58 μm . Molecular modeling was carried out through docking the designed compounds into the urease binding site to predict whether these derivatives have analogous binding mode to the urease inhibitors. The study revealed that all of the tested compounds bind with both metal atoms at the active site of the enzyme. The aromatic ring of the compounds forms ionic interactions with the residues, Ala(440), Asp(494), Ala(636), and Met(637).     

Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.     

Selective, centrally acting serotonin 5-HT2 antagonists. 2. Substituted 3-(4-fluorophenyl)-1H-indoles.

A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).     

FK506-binding protein ligands: structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5-dimethyl-2-(4-thiazolidine)carboxylates

Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)-5,5-dimethyl-1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine)carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.     

1-[3-(Diarylamino)propyl]piperidines and related compounds, potential antipsychotic agents with low cataleptogenic profiles

On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).     

Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors

As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.     

Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles.

A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rats were inhibited by most derivatives as a measure of central 5-HT2 receptor antagonism. Piperazinyl and tetrahydropyridyl indoles were cataleptogenic, while piperidyl substituted indoles surprisingly were found to be noncataleptogenic or only weakly cataleptogenic. Noncataleptogenic piperidyl derivatives also failed to block dopaminergic-mediated stereotypies, that is methyl phenidate-induced gnawing behavior in mice. These profiles resemble that of the atypical neuroleptic clozapine. 1-Ethyl-2-imidazolidinone was found to be the optimal substituent of the basic nitrogen atom in order to avoid catalepsy. The atypical neuroleptic 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] ethyl]-2-imidazolidinone (sertindole, compound 14c) was selected for further development as a result of these structure/activity studies.     

Design, synthesis and antihistaminic (H1)activity of some condensed 2-(substituted)arylaminoethylpyrimidin-4(3H)-ones

The synthesis and potential H1 receptor antagonistic activity of two novel series of condensed 2-arylaminoethylpyrimidin-4(3H)-ones (4, 5) and 4-amino-2-arylaminoethyl pyrimidines (6) have been reported. All the novel compounds were found to antagonize histamine in a competitive and reversible manner. When tested on guinea-pig ileum, compounds exhibited H1-antagonistic activity, (pA2 values) in the range of 8.6 to 9.7. Some of the lead compounds were evaluated by an in vivo method and were found to protect the guinea pigs against the histamine induced asphyxic shock at the doses comparable to or lower than those of the standard drugs, cetirizine (CAS 83881-51-0) and terfenadine (CAS 50679-08-8). The pA2 acetylcholine values of some of the lead compounds reflect about 1000-fold selectivity for histamine (H1) receptors. The 4-aminopyrimidines (6) were found to be more selective than their 4-one analogs (4, 5). In the radioligand binding study, one of the lead compounds, 6e, was found to bind reversibly at the histamine H1 receptor with the K1 value of 1.3 mumol/l and IC50 of 3.8 mumol/l. The lead compounds were found to have negligible sedative potential when tested in vivo. An indirect type of molecular modeling approach, using temelastine (CAS 86181-42-2) as the standard ligand, indicates that the potent activity of 4, 5 and 6 may be due to the increased spacer chain length between the pyrimidine nucleus and the side-chain aromatic ring.     

Substituted-vinyl hydroxytriarylethylenes, 1-[4-[2-(diethylamino) ethoxy]phenyl]-1-(4-hydroxyphenyl)-2-phenylethylenes: synthesis and effects on MCF 7 breast cancer cell proliferation

A series of triarylethylene compounds related to 4-hydroxyclomiphene (2) in which the vinyl Cl substituent was replaced by ethyl (5), Br (6), H (7), CN (8), or NO2 (9) substituents were synthesized to facilitate studies of the molecular actions of synthetic nonsteroidal antiestrogens. The relative binding affinities of these compounds for the estrogen receptor (ER) and the antiestrogen binding site (AEBS) in MCF 7 human mammary carcinoma cells were measured and correlated with the effects of these drugs on cell proliferation kinetics. Affinities for ER and AEBS were highly correlated, illustrating that vinyl substituents influence binding to ER and AEBS in a parallel manner. All compounds except 7 had biphasic effects on cell proliferation kinetics, indicating the presence of at least two distinct mechanisms by which hydroxytriarylethylenes inhibit breast cancer cell proliferation. In the concentration range 10(-10)-10(-8) M, cell proliferation was inhibited by 60-70%, these effects were estrogen-reversible, and the degree of growth inhibition was in the order Cl greater than Et greater than Br greater than NO2 greater than CN greater than H, which paralleled the order of affinities for ER. There was no further inhibition of cell growth between 10(-8) and 10(-6) M, but at concentrations greater than 10(-6) M there was a further dose-dependent decrease in cell growth mediated by mechanisms yet to be defined but apparently distinct from ER-mediated events. In both concentration ranges, growth inhibition was accompanied by accumulation of cells in the G1 phase of the cell cycle. These data, obtained with a novel series of hydroxytriarylethylenes, have enabled clear definition of two distinct mechanisms of growth inhibition by triarylethylene antiestrogens. They also indicate that among the vinyl substitutions examined to date the Cl substituent yields the most active molecule both in terms of affinity for ER and AEBS and potency as a growth inhibitory agent.     

Synthesis and biological evaluation of analogues of 7-chloro-4,5-dihydro-4- oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (TQX-173) as novel selective AMPA receptor antagonists

In recent papers (Catarzi, D.; et al. J. Med. Chem. 2000, 43, 3824-3826; 2001, 44, 3157-3165) we reported chemical and biological studies on 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) bearing different nitrogen-containing heterocycles at position-8. In particular, from these studies it emerged that both the 7-chloro-4,5-dihydro-4-oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a] quinoxaline-2-carboxylic acid TQX-173 (compound B) and its corresponding ethyl ester (compound A) were the most active and selective compounds of this series. In pursuing our investigation on the structure-activity relationships of these TQX derivatives, different electron-withdrawing groups (CF(3), NO(2)) were introduced at position 7 on the TQX ring system, replacing the 7-chloro substituent of B and of other selected 8-heteroaryltriazoloquinoxaline-2-carboxylates previously described. All the newly synthesized compounds were biologically evaluated for their binding at the Gly/NMDA, AMPA, and KA high-affinity receptors. Gly/NMDA binding assays were performed to assess the selectivity of the reported compounds toward the AMPA receptor. Compounds endowed with micromolar binding affinity for the KA high-affinity binding site were also evaluated for their binding at the KA low-affinity receptor. Some selected compounds were also tested for their functional antagonist activity at the AMPA and NMDA receptor-ion channel complex. The results obtained in this study have pointed out that 4,5-dihydro-7-nitro-4-oxo-8-(3-carboxypyrrol-1-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (9b) and its corresponding ethyl ester (9a) are the most potent and selective AMPA receptor antagonists reported to date among the TQX series.     

Inhibition of brain choline acetyltransferase in vivo: (E)-1-methyl-4-(1-naphthylvinyl)-1,2,3,6-tetrahydropyridine hydrochloride (B115), a depot form of a potent inhibitor

The quaternary ammonium salt (E)-4-(1-naphthylvinyl)pyridine hydroxyethyl bromide (B111) and the tertiary amine salt (E)-1-methyl-4-(1-naphthylvinyl)-1,2,3,6-tetrahydropyridine hydrochloride (B115), both previously shown to protect against organophosphate (OP) toxicity, were examined in vivo for effects on rat brain choline acetyltransferase (CAT) activity and acetylcholine (ACh) levels. When administered iv, but not when given ip, B111 was able to inhibit brain CAT 29% and reduce brain ACh levels 25%, yet was unable to prevent soman-induced increases in ACh. B115, which may serve as a depot form of a quaternary ammonium analogue, was able to decrease CAT activity as much as 80% upon multiple ip administration. This CAT inhibitory potency was unprecedented for a tertiary amine salt of its structure. However, ACh levels were reduced by no more than 25% and B115 was ineffective in preventing soman- and sarin-induced increases in ACh. Since the degree of inhibition of CAT activity produced by B111 and B115 was not accompanied by a corresponding decrease in ACh levels, the protection afforded by these compounds against OP toxicity is most likely not related to CAT inhibition. B115 was also tested for its ability to affect cholinergic receptor binding. B115 was administered to rats ip, twice daily, at low doses throughout a 3-week period. Analysis of cortex tissue revealed a 45% increase in nicotinic receptor binding with no change in either total muscarinic receptor binding (M-1 and M-2) or high-affinity muscarinic receptor binding (M-2 alone).     

Beta-adrenergic blocking agents. 20. (3-Hydroxyprop-1-enyl)-substituted 1-(aryloxy)-3-(alkylamino)propan-2-ols

The synthesis of a series of (3-hydroxyprop-1-enyl)-substituted 1-(aryloxy)-3-(alkylamino)propan-2-ols is described. These compounds were investigated for their beta-adrenoreceptor blocking properties and their selective of action. Among the o-(hydroxypropenyl)-substituted derivatives we have found some potent noncardioselective beta-adrenoreceptor blocking agents which have a greater blocking action on the beta 2 receptor, thus resembling propranolol. The p-(hydroxypropenyl)-substituted analogues were generally less potent and tended to be cardioselective. The structure-activity relationships are discussed in the light of the hypothesis that the cardioselective of p-amido-substituted (aryloxy)propanolamines is attributable, in part, to binding of the amide group to some additional site on the beta receptor; our findings argue against a similar interaction for the allylic hydroxyl group.     

Novel cerebroprotective agents with central nervous system stimulating activity. 2. Synthesis and pharmacology of the 1-(acylamino)-7-hydroxyindan derivatives.

In a continuous search for a novel cerebroprotective drug with a central nervous system (CNS) stimulating activity, a series of 1-(acylamino)-7-hydroxyindan derivatives has been synthesized and tested for its dual activities. The cerebroprotective activities of the compounds in this series were evaluated in terms of their effect on the survival of mice in hypoxic conditions (210 mmHg), and their CNS stimulating activities were examined by evaluating their promotional effects on the recovery from coma induced by cerebral concussion in mice. Several compounds prolonged the survival of mice in the hypoxic conditions at a dose of 30 mg/kg po. Four compounds in this series showed the CNS-stimulating effect at the same dose. Among them, 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetyl]amino]-2,2,4, 6-tetramethylindan (18, OPC-14117), which was active in the two tests with no side effect up to 500 mg/kg po daily for 2 weeks of administration to rats, was selected for preclinical investigations.     

Synthesis, 5-HT1A and 5-HT2A receptor affinity of new 1-phenylpiperazinylpropyl derivatives of purine-2,6- and pyrrolidine-2,5-diones

Two series of 1-phenylpiperazinylpropyl derivatives 10, 11, 16, 17 and 19-24, structurally related to previously described 5-HT1A or 5-HT2A ligands 4 and 1, respectively, were synthesized and their binding properties were determined. Structural modifications which involved 1,3-diazepine ring opening in 4 (compounds 10, 11, 15, 16) and replacement of spiroalkyl moiety in 1 by aryl substituent (19-24) did not improve binding affinity and selectivity of the tested compounds. The results showed, however, that the diazepine ring present in 4 or spiroalkyl ring in 1 are important for high 5-HT1A or 5-HT2A binding affinity and selectivity of these compounds.     

Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and alpha-adrenolytic activity

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the alpha(1)- and alpha(2)-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK(i) = 6.71 for alpha(1)-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50 )value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.     

3-(1-Indolinyl)benzylamines: a new class of analgesic agents

An extensive series of 3-(1-indolinyl)benzylamines and related compounds was synthesized and tested for analgesic activity. After a detailed study of structure-activity relationships, 3-(1-indolinyl)benzylamine (2b) was selected for further investigation as the most interesting member of this novel class of compounds. It was active in both the phenylquinone writhing and tail-flick assays for analgesic activity. No motor deficits were observed in the rotorod test, and 2b was found to be free of any other effects on the central nervous system. The compound did not bind to opiate receptors, since it was inactive in inhibiting the stereospecific binding of [3H]naloxone in rat brain homogenates. Thus, 3-(1-indolinyl)benzylamine represents a novel analgesic with an unusual chemical structure and biological profile.     

Interaction between substituted 1-[2-(diphenylmethoxy)ethyl] piperazines and dopamine receptors

Substituted 1-[2-(diphenylmethoxy)ethyl]piperazines were tested for their affinity to specific [³H]dopamine binding sites in membrane preparations from the corpus striatum of the rat. In particular, 4-(3-phenyl-2-prop(en)yl)- and 4-(3-phenyl-2-butyl)-substitution yielded compounds potent in displacing [³H]dopamine from its binding sites, with IC₅₀-values in the order of 10 nM. There was a significant correlation between the IC₅₀-values determined in this binding assay and the IC₅₀-values obtained for the same compounds in a previous study on their potency to inhibit the uptake of dopamine in synaptosomal preparations of the striatum of the rat. Current insight in structural requirements for binding to dopamine receptors, as obtained mainly with rigid analogues of dopamine, gives no satisfactory explanation for the dopaminergic activity of the piperazine derivatives tested.