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

• Autorzy: Wesołowska A.

Warianty tytułu

EN

Pharmacophore groups of the arylpiperazine ligands of serotonin 5-HT(1A) receptors

• Języki publikacji: PL

Abstrakty

EN

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.

Słowa kluczowe

PL

receptory 5-HT1A; ligandy receptorów 5-HT(1A); badania farmakologiczne

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2000
• Tom: [Z] 54, 5-6
• Strony: 457--472
• Opis fizyczny: schem., bibliogr. 51 poz.

Twórcy

autor

Wesołowska A.

• Zakład Badań Nowych Leków, Instytut Farmakologii PAN ul. Smętna 12, 31-343 Kraków

• Zakład Badań Nowych Leków, Instytut Farmakologii PAN, ul. Smętna 12, 31-343 Kraków

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Uwagi

PL

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