Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
J Med Chem. 2011 Oct 13;54(19):6704-13. doi: 10.1021/jm200585k. Epub 2011 Sep 16.
The novel class of spirocyclic σ(1) ligands 3 (6',7'-dihydro-1'H-spiro[piperidine-4,4'-pyrano[4,3-c]pyrazoles]) was designed by the combination of the potent σ(1) ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1', 1, and 6'. Whereas the small electron rich methylpyrazole heterocycle was less tolerated by the σ(1) receptor protein, the introduction of a phenyl substituent instead of the methyl group led to ligands with a high σ(1) affinity. It is postulated that the additional phenyl substituent occupies a previously unrecognized hydrophobic region of the σ(1) receptor resulting in additional lipophilic interactions. The spirocyclic pyranopyrazoles are very selective against the σ(2) subtype, the PCP binding site of the NMDA receptor, and further targets. Despite high σ(1) affinity, the cyclohexylmethyl derivative 17i (K(i) (σ(1)) = 0.55 nM) and the isopentenyl derivative 17p (K(i) (σ(1)) = 1.6 nM) showed only low antiallodynic activity in the capsaicin assay.
新型螺环σ(1)配体 3（6'，7'-二氢-1'H-螺[哌啶-4,4'-吡喃并[4,3-c]吡唑]）是通过将两种强效的σ(1)配体 1 和 2 结合在一个分子中设计而成的。通过改变 1'、1 和 6'位的取代基，得出了透彻的结构亲和力关系。虽然小的富电子甲基吡唑杂环较少被σ(1)受体蛋白耐受，但用苯基取代基代替甲基取代基会导致具有高σ(1)亲和力的配体。据推测，额外的苯基取代基占据了σ(1)受体中以前未被识别的疏水区，从而导致了额外的亲脂相互作用。螺环吡喃并吡唑对 σ(2)亚型、NMDA 受体的 PCP 结合位点和其他靶点具有很高的选择性。尽管环己基甲基衍生物 17i（K(i) (σ(1)) = 0.55 nM）和异戊烯基衍生物 17p（K(i) (σ(1)) = 1.6 nM）具有很高的σ(1)亲和力，但在辣椒素测定中，它们仅表现出低的抗痛觉过敏活性。
