Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0804, USA.
Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA, 92161, USA.
Psychopharmacology (Berl). 2019 Mar;236(3):989-999. doi: 10.1007/s00213-019-05207-1. Epub 2019 Mar 23.
Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute.
Here, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites.
2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α-adrenoceptor subtypes. 2-AI had particularly high affinity for α receptors (K = 41 nM) and slightly lower affinity for the α (K = 134 nM) and α (K = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT receptor.
2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability.
在过去的十年中,许多新的苯丙胺类兴奋剂类似物出现在娱乐性药物市场上,其中大多数是安非他命或卡西酮的衍生物。另一类设计药物源自 2-氨基茚满结构模板。这个类别的几个成员,包括母体化合物 2-氨基茚满(2-AI),已作为设计药物出售。另一种氨基茚满衍生物,5-甲氧基-2-氨基茚满(5-MeO-AI 或 MEAI),是一种在网上销售的作为酒精替代品的产品的有效成分。
在这里,我们测试了 2-AI 及其环取代衍生物 5-MeO-AI、5-甲氧基-6-甲基-2-氨基茚满(MMAI)和 5,6-亚甲基二氧基-2-氨基茚满(MDAI)与多巴胺(DAT)、去甲肾上腺素(NET)和血清素(SERT)的血浆膜单胺转运体相互作用的能力。我们还比较了氨基酸在 29 个受体和转运体结合位点的结合亲和力。
2-AI 是 NET 和 DAT 的选择性底物。环取代增加了 SERT 的效力,同时降低了 DAT 和 NET 的效力。MDAI 对 SERT 具有中等选择性,对 DAT 的作用弱十倍,对 NET 的作用弱十倍。5-MeO-AI 对 SERT 具有一定的选择性,对 NET 的效力低六倍,对 DAT 的效力低二十倍。MMAI 对 SERT 高度选择性,对 NET 和 DAT 的效力低 100 倍。氨基酸对α-肾上腺素能受体亚型具有相对高的亲和力。2-AI 对 α 受体具有特别高的亲和力(K=41 nM),对 α(K=134 nM)和 α(K=211 nM)亚型的亲和力略低。5-MeO-AI 和 MMAI 对 5-HT 受体也有中等亲和力。
预计 2-AI 具有(+)-安非他命样作用和滥用潜力,而环取代衍生物可能产生 3,4-亚甲基二氧基甲基苯丙胺(MDMA)样作用,但滥用的可能性较小。