Wyniki wyszukiwania - BazTech

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Synthesis of 3,3- and 4,4-Alkyl-phenyl-substituted Pyrrolidin-2-one Derivatives

Kulig K., Ignasik M., Malawska B.

Polish Journal of Chemistry

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2009

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Vol. 83, nr 9

1629-1636

EN

Syn the ses of 3,3- and 4,4-alkyl-phenyl-substi tuted pyrrolidin-2-one derivatives are described. The final compounds were obtained by the reductive cyclization of relevant cyanoalkanoate esters using NaBH4 and CoCl2×6H2O. The obtained pyrrolidin-2-one derivatives are pharmacophoric fragments for the syn thesis of various biologically active compounds.

2

Synthesis of the Enantiomers of 1-{2-Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one Using Soluble and Polystyrene Bound SalenCo(III)OAc Complexes as Catalysts of Hydrolytic Kinetic Resolution

Kulig K., Nowicki P., Malawska B.

Polish Journal of Chemistry

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2007

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Vol. 81, nr 2

179-186

EN

The asymmetric synthesis of 1-{2-hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-1-yl]- propyl}-pyrrolidin-2-one 3 is described. Enantiomers of compound 3 were synthesized by hydrolytic kinetic resolution (HKR) of racemic 1-oxiranylmethyl-pyrrolidin-2-one rac-2 using soluble or polystyrene bound salenCo(III)OAc complexes folowing its aminolysis with 1-(2-hydroxy-phenyl)-piperazine. The enantiomeric purity of obtained dihydrochloride salts of compounds 3was determined by HPLC method with Chiralpack IA column. The ees determined for enantiomers of compound 3 were in range 92–96% and indicated that proposed methods are effective tools for the synthesis of aminoalcohols. The application of polystyrene bound catalyst of HKR enables its easy isolation from reaction mixture and recovery.

3

Ligandy receptorów gabaergicznych : struktura, właściwości, możliwość zastosowania w terapii

Malawska B., Więckowski K.

Wiadomości Chemiczne

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2004

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[Z] 58, 7-8

571--598

EN

This review attempts to briefly summarize the recent development in the study of ?-aminobutyric (GABA) receptors, and their ligands. The search on compounds with agonistic and antagonistic properties of GABA receptors, the structure activity relationships, and therapeutic prospects of GABA receptors ligands was also described. GABA is the major inhibitory neurotransmitter in the brain [1-6], and influences neurons via a large number of receptor subtypes which are grouped on the basis of their pharmacology under three major classes of receptors: GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ligand gated ion channels, while GABAB receptors are G-protein coupled receptors [7-10]. These receptors, especially GABAA receptors, are involved in neurological and psychiatric disorders, and are therapeutic targets in certain diseases. Several different binding sites on GABAA receptors were proposed, these include agonist sites [11-14], which also recognize competitive antagonists [15], and many positive or negative modulators sites [16-20]. GABAA receptors are modulated by benzodiazepines [21-26], barbiturates, neurosteroides [27], klomethiazol [28, 29], anesthetics [30-33], ethanol [34], some insecticides [35], furosemide [36], Zn2+ iones [37], and sites for other compounds [38-40]. Some ligands of GABAB and GABAC receptors are also presented [41-44].

4

Poszukiwanie nowych selektywnych antagonistów receptorów α1 adrenergicznych

Malawska B., Kulig K.

Wiadomości Chemiczne

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2003

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[Z] 57, 3-4

267--288

EN

α1,-Adrenergic receptors (α1-AR) are members of the superfamily of G protein coupled receptors that transduce signals across the cell membrane. α1-ARs are comprised of multiple subtypes that have been identified by both pharmacological and binding studies [1], To date, they are classified into α1A, α1B, and α1D and the corresponding cloned counterparts termed α1a, α1b, and α1dAR, respectively. These subtypes have different tissue distributions with the α1A receptors predominating in lower urinary tract tissue, whereas this receptor subtype is less prevalent in the vasculature [2-4]. In recent years, the search for new selective α1-AR antagonists has intensified, due to their importance in the treatment of hypertension and of benign prostatic hyperplasia (BPH) [5-7]. Tamsulosin, the first α1A-AR „selective” antagonists for the treatment of BPH, was approved in 1997 [9, 12], A number of α1A subtype selective antagonists representing different structural classes of compounds were disclosed recently. These include: quinazolines [8-13], phenylalkylamines [9, 12, 14], piperidines [9, 15-23], arylpiperazines [24-36] and related compounds [37, 38], A review on the development of α1, selective antagonists are presented.

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Kierunki poszukiwania nowych leków wpływających na procesy uczenia i zapamiętywania, poprawiających rozpoznawanie

Malawska B.

Wiadomości Chemiczne

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2001

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[Z] 55, 1-2

67-92

EN

This review attempts to briefly summarise the recent developments in the study of new compounds improving learning, memory and cognitive function. A large number of compounds belonging to many different chemical classes have been proposed as cognition enhancers. Three groups of compounds - nootropics, cholinergic drugs and neuromodulators are presented . Most compounds described as nootrpics are 2-pyrrolidone derivatives, the prototype of which is piracetam (Nootropil) . Nootropics facilitate learning and memory in animal models. Clinical trials have yielded unconvincing results, however some new drugs such as nefiracetam and fasoracetam appear promising. Central cholinergic systems have been repeatedly shown to play an important role in learning and memory. The deficits in cognitive and memory performance observed in aged humans and in Alzheimer's disease (AD) patients are due at least in part to deficient cholinergic functioning. Augmentation of cholinergic neurotransmission might be accomplished in several different ways. Cholinergic agonists directly acting on muscarinic receptors may improve the defective cholinergic function seen in AD. Selective second-generation muscarinic agonists appear promising and are in various stages of preclinical and clinical evaluation, including milameline, itameline, xanomeline, sabcomeline and talsaclidine. These compounds are chemically related to the naturally occurring muscarinic agonist, arecoline. The prototypical neuronal acetylcholine receptors agonist nicotine has been shown to ameliorate some of the symptoms of AD, and, in a number of animal models, to have neuroprotective effects. Some nicotinic agonists were reported to be active in animal models of memory and learning, such as compounds ABT-418, ABT-089 and SIB-1553A . Acetylcholinesterase (AChE) inhibition is presently the most successful method to ameliorate cholinergic deficit and lead to symptomatic improvement. About 30 AChE inhibitors are currently being studied word-wide in preclinical or clinical studies. AChE inhibitors are broadly classified in three categories. These include: the carbamates such as physostigmine, eptastigmine, phenserine and rivastigmine; the aminoacridines such as tacrine, velnacrine, suronacrine, and their derivatives ipidacrine and compound SM-10888 ; the benzylpiperidines such as donepezil, T-82, TAK-147 and CP-118954. Tacrine was the the first drug approved in 1993 in USA for treatment of senile dementia of the Alzheimer type. Rivastigmine, and donepezil were approved in 1997. Cymserine and bis-norcimserine are derivatives of the alkaloid physostigmine. These compounds represent the first available potent, reversible, and selective inhibitors of butyrylcholinesterase. The organophosphate metrifonate has been extensively studied in animals and recently evaluated in AD. Metrifonat is an inactive prodrug, but is non-enzymatically transformed into the active compound dichlorvos that irreversibly inhibits AChE. There are many reports on the interaction between the cholinergic system and other putative neurotransmitter on the central nervous system. Therefore, such transmitter interactions play an important role in the regulation of learning and memory. Modulators, the third group of compounds represents different structures. A wide variety of substances have been shown to facilitate memory, including: opioid agonist (SA 4503), a benzodiazepine inverse agonist (S-8510), modulator of noradrenergic transmission (CR 2249) ; derivatives of piperazine (FK-960, ensaculine) and peptides (NC-1900) .

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Badania analogów kwasów [gamma]-amino i [gamma]-hydroksymasłowego o przewidywanym działaniu przeciwdrgawkowym

Malawska B.

Wiadomości Chemiczne

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2001

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[Z] 55, 3-4

377-402

EN

In the search for new anticonvulsants, derivatives of a-substituted g-amino-, g-phthalimido-, and g-hydroxybutyric acid such as acids, esters and amides were obtained. Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay for all synthesized compounds were employed. It was shown that a-substituted N-benzylamides of g-hydroxybutyric acid (GHB) were the most potent compounds and possessed anticonvulsant activities in the (MES) screens. The most potent anticonvulsant compounds were a-(benzylamino)- g-hydroxybutyric acid N-benzylamide and N-(2-chlorobenzylamide) with medium effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively . These compounds were less active then the commonly used anticonvulsants carbamazepine and phenytoin, but had higher activity in the MES screen than sodium valproate. The preliminary biochemical tests suggest that the active amides are acted as an allosteric modulator of the g-aminobutyric acid, GABA-A complex, and have the affinity to voltage sensitive calcium channels (VSCC) receptors. It may be the possible mechanism which mediates the anticonvulsant effect of these compounds. Four series of N-benzylamides of GHB, which contained the N-(4-phenylpiperazine)- (series A), N-(4-benzylpiperazine)- (series B), N-benzylamino-(series C), or N-(2-phenylethylamine)- (series D), group in the a-position of GHB were selected as models to found out the structural elements and/or physicochemical properties responsible for their anticonvulsant action. The lipophilicities of four anticonvulsant active series of compounds were determined by reversed-phase thin-layer chromatography (RM value) . 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 calculation of clog P values. It was found that anticonvulsant activity of amides series A-D may be explained on the basis of their lipophilicity. 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 compounds of series A and B. Molecular modelling investigations were carried out using computer program on the representative compounds of series A-D. Based on the pharmacological, physicochemical, rentgenostructural and molecular modelling results the pharmacophore model for anticonvulsant N-substituted amides of GHB was design. In this model, the presence of the N-benzylamide fragment is essential for activity. For amides the further elements are hydrophobic unit (aryl ring) as a distal binding site and H-bond as a donor function. Based on this model new compounds with expected anticonvulsant activity may be design.