NPY Y1 antagonists: structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures.

Previously, omega-guanidino- and omega-aminoalkanamides, structurally derived from arpromidine-like histamine H2 receptor agonists, were reported as novel neuropeptide Y Y1 antagonists. Regardless of the backbone, they resemble BIBP 3226, an argininamide with high NPY Y1 receptor affinity and selectivity, with respect to nature and arrangement of the 'terminal' diaryl, guanidine, and hydroxyphenyl groups. Hybrid compounds were synthesized combining the argininamide backbone of BIBP 3226 or partial structures derived from the C-terminal dipeptide of NPY with characteristic substructures of arpromidine- or amide-type NPY antagonists. Additionally, some analogs of BIBP 3226 with reduced flexibility were prepared. Structure-activity relationships indicate that, in contrast to alkanamides, homologs and/or isomers of BIBP 3226 with vicinal arrangement of the phenyl rings have decreased Y1 antagonistic activity (Ca2+-assay in HEL cells). Replacement of the hydroxybenzyl group by an imidazole ring further decreases activity. It is concluded that the binding sites of NPY antagonists with one and with two basic groups are not identical. Analogs with a rigid tetrahydro-2-benzazepine or an indan group in place of the benzyl moiety in BIBP 3226 are active, indicating the role of the OH group and supporting the model proposed for the interaction of BIBP 3226 with the Y1 receptor.

Search for new anticonvulsant compounds. Part 1: Synthesis, physicochemical and anticonvulsant properties of new derivatives of alpha-amino-gamma-phthalimidobutyric acid.

Synthesis and physicochemical properties of new derivatives of alpha-substituted gamma-phthalimidobutyric acid are described. N-substituted amides of alpha-(4-phenylpiperazine)-gamma- phthalimidobutyric acid were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of BOP reagent. 2-(4-Phenylpiperazine)- or 2-(4-benzylpiperidine)-4-phthalimidobutyric acid were esterified with alkyl bromide in the presence of DBU or tetrabutylammonium bromide as catalyst. The obtained compounds were evaluated for anticonvulsant activity. 2-(4-Phenylpiperazine)-4-phthalimidobutyric acid and three N-substituted amides of this acid displaced protection against MES and scMet-induced seizures.

Synthesis, physicochemical properties, anticonvulsant activities and voltage-sensitive calcium channels affinity of N-substituted amides of alpha-(4-phenylpiperazino)-GABA. Part 3: Search for new anticonvulsant compounds.

This paper describes the synthesis and preliminary anticonvulsant evaluation of some GABA analogues i.e. derivatives of 2-(4-phenylpiperazino)- or 2-(4-benzylpiperidino)-GABA (5, 6), N-substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobutyric acid and N-substituted amides of 2-(4-phenylpiperazino)-GABA. N-Substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobutyric acid (7-11) were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of different coupling reagents (2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and carbonyldiimidazole (CDI). N-Substituted benzylamides of 2-(4-phenylpiperazino)-4-aminobutyric acid (12-14) were prepared by hydrazinolysis of amides 9-11. Anticonvulsant activities were determined in mice (for all compounds) and in rats using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The amides (12-14) showed protection against MES and/or scMet seizures in mice. N-(4-Methoxybenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide (13) was the most effective and displayed anticonvulsant activity in both tests at doses of 100-300 mg/kg in mice and at 30 mg/kg in the MES screen in rats. The active compounds (12-14) were tested for their ability to displace [3H]nitrendipine binding sites (voltage-sensitive calcium channel receptors) from rat cortex. Amide 13 was the most active both in pharmacological and biochemical tests. These preliminary results suggest that the anticonvulsant activity of compounds 12-14 may be related to their influence on voltage-sensitive calcium channel receptors.

Determination of the lipophilicity of active anticonvulsant N-substituted amides of alpha-arylalkylamine-gamma-hydroxybutyric acid.

The lipophilicities of fourteen anticonvulsant active N-substituted amides of alpha-arylalkylamine-gamma-hydroxybutyric acid [I-XIV] have been determined by reversed-phase thin-layer chromatography with a mixture of methanol, TRIS buffer, and acetic acid as the solvent system. The RM value of each compound decreased linearly with increasing concentration of methanol. The partition coefficients (log P) of the amides were calculated by use of the Prolog P module of the Pallas system. Comparison of RM and log P enabled clog P values to be calculated. It was found that the anticonvulsant activity of amides [I-XIV] can be explained on the basis of their lipophilicity.

Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors.

The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacridines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman's spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation.

Multi-target-directed ligands in Alzheimer's disease treatment.

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid ß peptide (Aß) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aß plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and ß-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

Influence of the absolute configuration on pharmacological activity of antihypertensive and antiarrhythmic drugs.

Chirality is a fundamental property of biological systems and reflects the underlying asymmetry of matter. Interactions of drugs with receptors, enzymes or binding sites have long been known to be stereoselective, and it is increasingly recognized that both pharmacodynamic and pharmacokinetic events contribute to the overall clinically observed stereoselectivity. The pharmacological activity may reside only in one enantiomer, while the second one may be inactive or have desirable or undesirable activity. Two isomers may be nearly identical both in qualitative and quantitative aspects of pharmacological activity. The activity of particular enantiomers may differ only at the quantitative level. It is also possible that a particular enantiomer displays qualitatively different mode of action than the second one. This review describes the influence of the absolute configuration on pharmacological activity of the selected currently used or being under investigation drugs acting on cardiovascular system, especially as the antihypertensive and antiarrhythmic agents.

Synthesis, physicochemical and preliminary pharmacological properties of N-[beta-hydroxy-gamma-(N-phenylpiperazinepropyl)]-2-pyrrolidinone.

The present paper reports on the synthesis and preliminary pharmacological properties of N-[beta-hydroxy-gamma-(N-phenylpiperazinepropyl)]-2- pyrrolidinone (MG-1). MG-1 was obtained by aminolysis of 1-(beta, gamma-epoxypropyl)-2-pyrrolidinone and N-phenylpiperazine. Its structure was established by elemental and spectral analyses (IR, UV, MS, 1H, 13C, 2D H-H and 2D C-H NMR). The antiarrhythmic activity of MG-1 was investigated on mice, rats and guinea pigs, using several models of arrhythmia. MG-1 attenuated or prevented the adrenaline- and barium chloride-induced arrhythmia. MG-1 demonstrated potent local anesthetic properties and depressed the depolarization phase of the action potential of cardiac cells. These results indicate that MG-1 possesses antiarrhythmic activity.

The structure-activity relationship of a new anti-arrhythmic agent 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one.

This paper reports the synthesis of the new compound 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one (Ac-MG-1). Preliminary pharmacological assessment revealed that Ac-MG-1 possesses anti-arrhythmic activity and a local anesthetic effect. The crystal structure of Ac-MG-1 was determined by X-ray diffraction, and conformational analysis was performed both for Ac-MG-1 and for other derivatives of (arylpiperazinyl)propylpyrrolidin-2-one.

Synthesis and pharmacological properties of new N-aminoalkyl-2-pyrrolidinone derivatives.

The paper describes the mode of obtaining and physico-chemical properties of new 1-(beta-hydroxy-gamma-aminopropyl)-2-pyrrolidinone derivatives and their antiarrhythmic effect and the action on the circulatory system.

Search for New Anticonvulsant Compounds, Part 2. Structure-activity relationship studies of new N-substituted amides of alpha-piperazine-gamma-hydroxybutyric acid as active anticonvulsants.

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of alpha-(4-phenylpiperazine)-gamma-hydroxybutyric acid (A) and derivatives of N-benzylamides of alpha-(4-benzylpiperazine)-gamma-hydroxybutyric acid (B), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100-300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B.

Synthesis and pharmacological properties of 1,3 and 5-substituted 2-pyrrolidinones.

We described synthesis of 1-aryl-3 and 5-substituted 2-pyrrolidinones (2a--5a and 3b--4b). Pharmacological studies revealed that compounds 3b, 4a and 4b have analgetic and antiinflammatory properties. None of the compounds posesses neuroleptic or anticonvulsant properties.

Synthesis and pharmacological properties of some 2-pyrrolidinone Mannich bases.

N-aminoalkyl derivatives of 2-pyrrolidinone (1-5) and methylene-bis-amino derivatives (7-9) as intermediary products formed during aminoalkylation were described. Compounds 2 and 3, in doses over 30 and 20 mg/kg resp., displayed analgesic properties; compound 3 exerted also a weak anti-inflammatory action (37 mg/kg po) in the carrageenin test.

Synthesis and preliminary pharmacological assessment of novel gamma-hydroxybutyric acid derivatives.

Synthesis and properties of new N-substituted amides of alpha-(1,1-ethylenedioxy)-ethyl-gamma-hydroxybutyric acid are described. The compounds were obtained by aminolysis of 3-(1,1-ethylenedioxy)-ethyltetra-hydrofuran-2-on with primary alkylarylamines. Preliminary pharmacological assessment revealed that the compounds exert weaker influence on the central nervous system than the reference gamma-hydroxybutyric acid. Three of the novel compounds offered some protection against pentetrazole-induced tonic seizures in mice.

Search for new antiarrhythmic and hypotensive compounds. Synthesis, antiarrhythmic, antihypertensive, and alpha-adrenoceptor blocking activity of novel 1-[(2-hydroxy-3-amino)]-propylpyrrolidin-2-one derivatives.

A series of the derivatives of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl])propyl]-pyrrolidin-2- one (MG-1) was synthesized and tested for electrocardiographic, antiarrhythmic, and antihypertensive activity as well as for alpha 1- and alpha 2-adrenoceptors binding affinities. Some of the compounds of this series slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Only compound 7 (1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-pyrrolidine) possesses potent antiarrhythmic and a slight hypotensive properties, and affinity for alpha 1- and alpha 2-adrenoceptor. The results suggest that the antiarrhythmic and hypotensive effect of compound 7 and MG-1 is related to their adrenolytic properties, and that those properties depend on the presence of a phenylpiperazine moiety.

Synthesis, physicochemical properties, anticonvulsant activities, and GABA-ergic and voltage-sensitive calcium channel receptor affinities of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid. Part 4: Search for new anticonvulsant compounds.

In a search for new anticonvulsant compounds, two series of N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (series A) and alpha-(2-phenylethylamino)-gamma-hydroxybutyric acid (series B), were investigated in maximal electroshock (MES), subcutaneous metrazole, and rotorod toxicity assays. The most potent anticonvulsant compounds were alpha-(benzylamino)-gamma-hydroxybutyric acid N-benzylamide (3) and N-(2-chlorobenzylamide (4) with median effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively. alpha-(4-Phenylpiperazinyl)-gamma-hydroxybutyric acid N-(4-methylbenzyl)amide (17) and alpha-(benzylpiperazinyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)amide (18) were also tested for their ability to potentiate [3H]-muscimol binding and to inhibit [35S]-TBPS binding (as indices of GABA-A receptor potentiation). Amide 17 exhibited activity at the GABA-A complex which may be the mechanism by which the anticonvulsant effect of this compound is mediated. The N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (3-9) were also evaluated for their ability to displace [3H]-nitrendipine from voltage-sensitive calcium channel (VSCC) receptors isolated from rat cortex.

Influence of new gamma-aminobutyric acid amide derivatives and its phthalimide precursors on the central nervous system activity in mice.

The present study investigated the influence of BM-78, BM-121 (gamma-aminobutyric acid amide derivatives) and BM-42, BM-43 (phthalimide precursors of BM-78 and BM-121) on the spontaneous locomotor activity and on the picrotoxin-induced seizures. Results of pharmacological in vivo examination of the effects of new gamma-aminobutyric acid amide derivatives and its phthalimide precursors (compounds BM-78, BM-121, BM-42, BM-43), presented in this paper showed that all the compounds had different but clear influence on CNS in mice.