Synthesis and biological evaluation of 1,3-dioxolane-based 5-HT1A receptor agonists for CNS disorders and neuropathic pain

被引：9

作者：

Franchini, Silvia ^{[1
]}

Bencheva, Leda Ivanova ^{[1
]}

Battisti, Umberto Maria ^{[1
]}

Tait, Annalisa ^{[1
]}

Sorbi, Claudia ^{[1
]}

Fossa, Paola ^{[2
]}

Cichero, Elena ^{[2
]}

Ronsisvalle, Simone ^{[3
,4
]}

Arico, Giuseppina ^{[3
,4
]}

Denora, Nunzio ^{[5
]}

Iacobazzi, Rosa Maria ^{[6
]}

Cilia, Antonio ^{[7
]}

Pirona, Lorenza ^{[7
]}

Brasili, Livio ^{[1
]}

机构：

[1] Univ Modena & Reggio Emilia, Dipartimento Sci Vita, Via Campi 103, I-41125 Modena, Italy

[2] Univ Genoa, Dipartimento Farm, Viale Benedetto XV 3, I-16132 Genoa, Italy

[3] Univ Catania, Dipartimento Sci Farmaco, Sez Chim Farmaceut, Viale Andrea Doria 6, I-95125 Catania, Italy

[4] Univ Catania, Sez Farmacol & Tossicol, Viale Andrea Doria 6, I-95125 Catania, Italy

[5] Univ Bari Aldo Moro, Dipartimento Farm Sci Farmaco, Via E Orabona 4, I-70125 Bari, Italy

[6] Ist Tumori IRCCS Giovanni Paolo II, Via O Flacco 65, I-70124 Bari, Italy

[7] Recordati SpA, Div Ric & Sviluppo, Via Civitali 1, I-20148 Milan, Italy

来源：

FUTURE MEDICINAL CHEMISTRY | 2018年 / 10卷 / 18期

关键词：

5-HT1A receptor agonist; alpha(1)-adrenoceptors; antinociceptive activity; neuroprotection; STRUCTURE-AFFINITY/ACTIVITY RELATIONSHIPS; INDUCED DYSKINESIA; ANIMAL-MODELS; LIGANDS; DERIVATIVES; SEROTONIN; PREDICTION; DISCOVERY; ALPHA(1); DRUGS;

D O I：

10.4155/fmc-2018-0107

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aim: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control. Methodology: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at alpha(1)-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. Results & conclusion: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/alpha 1 = 135). in vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.

引用

页码：2137 / 2154

页数：18

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