Comparison of binding parameters of σb>1b> and σb>2b> binding sites in rat and guinea pig brain membranes: novel subtype-selective trishomocubanes

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• 作者：Nguyen ; Vu H. ; Kassiou ; Michael ; Johnston ; Graham A.R. ; Christie ; Macdonald J.
• 关键词：σ ; Binding site ; Trishomocubane ; (+)-Pentazocine ; 1 ; 3-Di-o-tolylguanidine ; Brain membrane
• 刊名：European Journal of Pharmacology
• 出版年：1996
• 出版时间：September 12, 1996
• 年：1996
• 卷：311
• 期：2-3
• 页码：233-240
• 全文大小：729 K

文摘

Comparisons of binding parameters of [³H](+)-pentazocine and [³H]1,3-di-o-tolylguanidine (DTG) at σ binding sites in guinea pig and rat brain membranes demonstrated that [³H](+)-pentazocine binds to a single high-affinity site, whereas [³H]DTG binds to two high-affinity sites in both species. The Kb>db> values of the radioligands were similar in both types of membranes. However, the density of σb>1b> sites in guinea pig was significantly higher than that of rat. Novel trishomocubanes were tested for their affinities at σb>1b> and σb>2b> binding sites in guinea pig brain membranes using [³H](+)-pentazocine and [³H]DTG as the radioligands. N-(4-Phenylbutyl)-3-hydroxy-4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecane (ANSTO-14) showed the highest affinity for the σb>1b> site (Kb>ib> = 9.4 nM) and 19-fold σb>1b>/σb>2b> selectivity, as a result of increasing the alkyl chain between the cubane moiety and the aromatic ring. N-(3′-Fluorophenyl)methyl-3-hydroxy-4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecane (ANSTO-19), displayed the highest affinity for σb>2b> sites (Kb>ib> = 19.6 nM) and 8-fold σb>2b>/σb>1b> selectivity due to a fluoro substitution in the meta position of the aromatic ring. These represent structurally novel lead compounds, especially for the development of selective σb>2b> receptor ligands.