Benzoquinolizine Derivatives: a New Class of Monamine Decreasing Drugs With Psychotropic Action

Pletscher, A.; Brossi, Arnold; Gey, K. F.

doi:10.1016/s0074-7742(08)60024-0

Cited by 170 publications

(62 citation statements)

References 46 publications

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“…Taken together, these results support the idea that VMAT2 should be considered as a valid target for the development of pharmacotherapies to treat psychostimulant abuse. Other evidence supporting the role of VMAT2 in psychostimulant pharmacology is the fi nding that benzoquinolizine derivatives, such as TBZ, which have high affi nity for VMAT2, decrease locomotor activity and aggressiveness in monkeys 55 and decrease methamphetamineinduced hyperactivity in rodent animal models. 55…”

Section: Vmat2 and Psychostimulant Abusementioning

confidence: 99%

“…These analogs retain good amine-depleting activity. 55 In vivo, TBZ is rapidly and extensively metabolized to its reduced form, DTBZ ( 3 , Figure 1 ). 67 [ 3 H]DTBZ (label on the C-2 hydrogen) has been used as a selective radioligand in in vitro brain homogenate binding studies and in autoradiographic studies, and is reported to have a K d value of 3.0 nM.…”

Section: Tbz and Its Analogsmentioning

confidence: 99%

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

Zheng

Dwoskin

Crooks

2006

AAPS J

107

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Section: Vmat2 and Psychostimulant Abusementioning

confidence: 99%

Section: Tbz and Its Analogsmentioning

confidence: 99%

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

Zheng

Dwoskin

Crooks

2006

AAPS J

107

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“…The main pathway for degradation of catecholamines is through monoamine oxidase. Pargyline (Hellerman & Erwin, 1968), the wellknown monoamine oxidase inhibitor which prevents the degradation of noradrenaline, and the drug Ro 4-1284, which increases the concentration of noradrenaline at the site by enhancing the rate of release (Pletscher et al, 1962), were used for this set of experiments. Results in Table 3 show that both the compounds tested effectively stimulated hepatic sterol biogenesis from acetate.…”

Section: Effect Ofagents That Increase Endogenous Noradrenalinementioning

confidence: 99%

Nature of the stimulation of biogenesis of cholesterol in the liver by noradrenaline

George¹,

Ramasarma²

1977

Biochemical Journal

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1. Administration of noradrenaline increased the incorporation of [1-14C]acetate into hepatic sterols and the activity of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase. 2. The stimulation was observed at short time-intervals with a maximum at 4h and was progressive with increasing concentrations of noradrenaline. 3. Protein synthesis de novo was a necessary factor for the effect. 4. The stimulatory effect was not mediated through the adrenergic receptors, but appears to involve a direct action of the hormone within the hepatocyte.

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“…Other evidence supporting the role of VMAT2 in psychostimulant pharmacology is the finding that benzoquinolizine derivatives, such as tetrabenazine, have high affinity for VMAT2, decrease locomotor activity and aggressiveness in monkeys, and, moreover, depress methamphetamine-induced hyperactivity in rats and mice. 13 (−)-Lobeline (2R,6S,10S; 1a) (Figure 1), a weakly basic lipophilic alkaloid from Lobelia inflata, interacts with VMAT2 and DAT via a novel mechanism of action. 14 15,16 Furthermore, lobeline also inhibits (IC 50 = 80 μM) [ 3 H]DA uptake into rat striatal synaptosomes via DAT, but with 100-fold lower affinity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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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.

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Benzoquinolizine Derivatives: a New Class of Monamine Decreasing Drugs With Psychotropic Action

Cited by 170 publications

References 46 publications

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

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

Nature of the stimulation of biogenesis of cholesterol in the liver by noradrenaline

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

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