Quinolyl analogues of norlobelane: Novel potent inhibitors of [³H]dihydrotetrabenazine binding and [³H]dopamine uptake at the vesicular monoamine transporter-2

We have previously shown that quinolyl moieties are attractive structural replacements for the phenyl groups in lobelane. These quinolyl analogues had improved water-solubility over lobelane and retained the potent vesicular monoamine transporter-2 (VMAT-2) inhibitory properties of the parent compound, with quinlobelane (4) exhibiting potent inhibition of uptake at VMAT-2 (K_i = 51 nM). However, the VMAT-2 inhibitory properties of quinolyl analogues of norlobelane, which is equipotent with lobeline as an inhibitor of [³H]dopamine (DA) uptake at VMAT-2, have not been reported. In the current communication, we describe the synthesis of some novel des-methyl quinolyl analogues of lobelane that exhibit greater affinity (K_i = 178-647 nM) for the dihydrotetrabenazine binding site located on VMAT-2 compared with lobelane (K_i = 970 nM), norlobelane (K_i = 2310 nM) and quinlobelane (K_i = 2640 nM). The most potent compounds, 14 and 15, also exhibited inhibition of [³H]DA uptake at VMAT-2 (K_i = 42 nM) which was comparable to both lobelane (K_i = 45 nM) and norlobelane (K_i = 43 nM). Results reveal that binding affinity at VMAT-2 serves as an accurate predictor of inhibition of the function of VMAT-2 for the majority of these analogues. These novel analogues are under consideration for further development as treatments for methamphetamine abuse.