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

Malawska B.

Wiadomości Chemiczne

2001

[Z] 55, 3-4

377-402

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.

Grupy farmakoforowe arylopiperazynowych ligandów receptorów serotoninowych 5-HT(1A)

Wesołowska A.

Wiadomości Chemiczne

2000

[Z] 54, 5-6

457-472

Of different subpopulations of G-coupled serotonin (5-HT) receptors, in the past decade the utmost attention has been focused on the 5-HT1A subtype. This review is concerned with the structure-activity relationships of some 5-HT1A receptor ligands belonging to the 1-arylpiperazine class. Literature data show that NAN-190, MM-77 and BMY 7378 which contain a 1-(o-methoxyphenyl)piperazine (1-MeOPhP) fragment have a very high 5-HT1A affinity and act as postsynaptic 5-HT1A receptor antagonists. It has been shown that the basic nitrogen atom and methoxy group in the arylpiperazine fragment are desired features of the structure for both the affinity and postsynaptic antagonism at 5-HT1A receptors, since (I) replacement of the 1-MeOPhP fragment by 1,2,3,4-tetrahydroisoquinoline (THIQ) causes a dramatic loss of the 5-HT1A affinity (cf. 1 vs BMY 7378, 2 vs MM-77, 3 vs NAN-190), (II) modifications of the amide fragment (cf. MM-77 and MM-55 vs NAN-190) have no significant effect on their functional activity; like NAN-190, MM-77 and MM-55 are postsynaptic 5-HT1A antagonists, and (III) replacement of the 1-MeOPhP fragment by the 1,2,3,4-tetrahydropyrazino[1,2-a]indolo system results in a significant loss of the 5-HT1A affinity and a lack of in vivo activity (cf. 4 vs NAN-190). Therefore it may be assumed that the 1-MeOPhP fragment present in the postsynaptic 5-HT1A antagonists plays a major role in the formation of a bioactive complex with 5-HT1A receptors. Another 5-HT1A ligand, buspirone - a second-generation anxiolytic - which contains a 1-(2-pyrimidynyl)piperazine (1-PP) fragment, is a postsynaptic 5-HT1A partial agonist. It is generally accepted that the buspirone molecule is recognized by the 5-HT1A receptor due to the presence of 1-PP. In other words, the 1-PP fragment of buspirone fulfills the minimal structure requirements defined by Hibert et al. for the interaction with the 5-HT1A binding site, one being the presence of an aromatic ring, and the other the presence of a basic nitrogen atom at a distance of 5.2-5.7 D. On the other hand, the terminal imide moiety offers an additional site of interaction with the 5-HT1A receptor, which results in a greatly enhanced affinity of buspirone in relation to 1-PP . The buspirone molecule is modified by replacing the 1-PP fragment with THIQ (compound MM199). Buspirone and MM199 are equipotent 5-HT1A ligands; moreover, MM199 has essentially the same functional profile at postsynaptic 5-HT1A receptors as does buspirone. Both these compounds are classified as partial agonists of postsynaptic 5-HT1A receptors. Furthermore, like buspirone, MM199 shows an antidepressant- and an anxiolytic-like activity in animal models. Its effects are antagonized by (S)WAY 100135, a 5-HT1A receptor antagonist, which suggests that potent antidepressant- and anxiolytic-like effects of MM199 are mediated by activation of 5-HT1A receptors. The obtained results permit a general conclusion that the basic nitrogen atom and the terminal bulky cycloimide moiety, but not the 2-pyrimidinyl group, are pivotal features of the buspirone structure, being directly involved in the formation of a bioactive complex with 5-HT1A receptors.