- Significant progress was made on this project, which involves the development of medications for psychiatric diseases, especially substance use disorders. Five relevant papers were published in peer-reviewed journals. In a key article, we show that phenyl ring-substitution of aminoindan analogs increases the potency at 5-HT transporters (SERT) relative to dopamine transporters (DAT) and norepinephrine transporters (NET). Aminoindans with greater activity at SERT might have utility as medications with reduced abuse potential. Over the last decade, many psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Many of these agents are similar to widely prescribed medications like methylphenidate and bupropion. 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, whereas others such as 5-methoxy-2-aminoindan (5-MeO-AI or MEAI) show promise as a treatments for alcoholism. 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 2-adrenoceptor subtypes. 2-AI had particularly high affinity for 2C receptors (Ki=41 nM) and slightly lower affinity for the 2A (Ki=134 nM) and 2B (Ki=211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B 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.
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