Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, I-70125 Bari, Italy.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Future Med Chem. 2019 Oct;11(19):2547-2562. doi: 10.4155/fmc-2019-0042.
The σ receptor is a druggable target involved in many physiological processes and diseases. To clarify its physiology and derive therapeutic benefit, nine analogs based on the σ antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity (.#x00A0;= 0.12, 0.31 or 1.03 nM). Calcium flux assays in MCF7σ cells indicated that the highest σ receptor affinity are σ antagonists. Molecular models provided a structural basis for understanding the σ affinity and functional activity of the analogs and incorporated Glennon's σ pharmacophore model. Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ receptor physiology.
σ 受体是一种可成药的靶点，涉及许多生理过程和疾病。为了阐明其生理学并获得治疗益处，基于 σ 拮抗剂 PB212 合成了 9 种类似物，用不同大小和构象自由度的碱性基团取代了 4-甲基哌啶。3-苯基吡咯烷、4-苯基哌啶或 granatane 衍生物显示出最高的亲和力（#x00A0;= 0.12、0.31 或 1.03 nM）。MCF7σ 细胞中的钙通量测定表明，最高的 σ 受体亲和力为 σ 拮抗剂。分子模型为理解类似物的 σ 亲和力和功能活性提供了结构基础，并纳入了 Glennon 的 σ 药效基团模型。在此，我们确定了新的化合物，可作为治疗药物先导或作为研究 σ 受体生理学的工具。
