Defunctionalized Lobeline Analogues:  Structure−Activity of Novel Ligands for the Vesicular Monoamine Transporter

Abstract

Abstract(−)-Lobeline (2R,6S,10S; 1a), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure-activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. Generally, all of these analogues had lower affinities at α4β2* and α7* nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the transseries. The most potent (K i = 630 nM) and VMAT2-selective compound evaluated was the Nmethyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue 28b (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure-activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a π-extended structure.

Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2

“…As expected, lobelane and meso-transdiene (MTD; Fig. 1) had little or no affinity for either ␣4␤2* or ␣7* nAChRs (Miller et al, 2004;Zheng et al, 2005). It is noteworthy that lobelane and MTD exhibited higher affinity for both DAT and VMAT2.…”

Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

“…Through an interaction with VMAT2, lobeline inhibits the neurochemical and behavioral effects of methamphetamine (Teng et al, 1997(Teng et al, , 1998Harrod et al, 2001;Miller et al, 2001;Dwoskin and Crooks, 2002;Nickell et al, 2010). Lobelane, a lobeline analog with greater selectivity for VMAT2, decreased both methamphetamineevoked DA release (IC 50 ϭ 0.65 M; I max ϭ 73.2%; same experimental conditions as the current work) and methamphetamine self-administration (Zheng et al, 2005a;Neugebauer et al, 2007;Beckmann et al, 2010;Nickell et al, 2010Nickell et al, , 2011. Unfortunately, further development of lobelane as an effective pharmacotherapy was hindered by unacceptable drug-likeness properties.…”

Vesicular monoamine transporter 2: Role as a novel target for drug development

“…The presence of a basic amine functionality is likely a prerequisite for VMAT2 recognition, as is evidenced by the fact that quaternized compounds 41 ( K i > 100 μM) and 42 ( K i = 16.5 μM) ( Figure 12 ) show signifi cant loss in affi nity for VMAT2. 124 The entire lobelane structure appears to be critical for highaffi nity binding at VMAT2, since fragments of lobelane or MTD, such as compounds 43 and 44 ( Figure 13 ) (both K i > 100 μM), exhibited no affi nity for VMAT2. 125 Isomerized lobelane analogs, such as compound 45 ( Figure 14 ) ( K i = 1.36 m M), retained affi nity for VMAT2, indicating that the position of the piperidine N atom relative to the C2 and C6 side chains does not appear to be critical for VMAT2 interaction, and that the VMAT2 binding site can tolerate changes in distance between the piperidine nitrogen and the 2 phenyl rings.…”