N‐Substituierte Bis‐(γ‐phenpropyl)‐amine

Stühmer, Werner; Elbrächter, Ernst‐August

doi:10.1002/ardp.19542870308

Cited by 4 publications

(2 citation statements)

References 4 publications

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“…Some of the compounds used in the present investigation were prepared according to previously published literature procedures; these include lobelanidine HCl ( 4 ), 7 HCl, 8 HCl, 9 HCl, (−)sedamine HCl ( 10 ), 32 11 HI, 12 hydrogen oxalate, and lobelan HCl ( 14 ) . Two other compounds were also prepared by literature procedures, but because their melting points differed somewhat from those reported in the literature they were submitted for elemental analysis; both analyzed correctly for C, H, and N and include lobelanine HCl ( 3 ; mp 203−205 °C, lit .…”

Section: Methodsmentioning

confidence: 99%

Lobeline: Structure−Affinity Investigation of Nicotinic Acetylcholinergic Receptor Binding

et al. 1999

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(-)Lobeline (1) and (-)nicotine (2) bind at neuronal nicotinic cholinergic (nACh) receptors with high affinity (K(i) = 4 and 2 nM, respectively). Previous attempts to determine whether lobeline fits the currently accepted nicotinic pharmacophore model have led to suggestions that the carbonyl function, rather than the hydroxyl group, is a major contributor to binding. Interestingly, however, it has never been empirically demonstrated that either oxygen function is actually required for interaction with the receptor. In the present investigation we systematically examined a number of abbreviated analogues of lobeline and found that removal of either one or both oxygen functions reduces the affinity of lobeline by at least 25-fold; furthermore, oxidation of the (-)lobeline hydroxyl group (to afford lobelanine) or reduction of the carbonyl group (to afford lobelanidine) also resulted in decreased affinity. Although it is likely that both oxygen functions contribute to the high affinity of (-)lobeline at nACh receptors, it is concluded that the presence of both oxygen functions is not a requirement for binding; that is, replacement of the (-)lobeline hydroxyl group with a chloro group had no effect on affinity. Another finding of the present investigation is that removal of either one or both oxygen functions of lobeline results in compounds that retain the analgesic activity and potency of (-)lobeline, indicating that there is no direct relationship between neuronal nicotinic cholinergic (primarily alpha(4)beta(2) type) receptor affinity and spinal analgesia as measured in the tail-flick assay.

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Section: Methodsmentioning

confidence: 99%

Lobeline: Structure−Affinity Investigation of Nicotinic Acetylcholinergic Receptor Binding

et al. 1999

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“…Ring-opened compounds 25a and 25b (Figure ) were obtained during the hydrogenation of 5b to 6b and of 5c to 6c , respectively, as byproducts. Acyclic compound 26 and 27 (Figure ) were prepared as previously reported. The nor-1-naphthyl and nor-2-naphthyl compounds 28a and 29a were prepared according to the procedure utilized to prepare norlobelane ( 20 ), except that 1- or 2-naphthaldehyde was used instead of benzaldehyde (Scheme ).…”

Section: Chemistrymentioning

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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Drugs for Functional Gastrointestinal Disorders (A03)

Kleemann¹

2020

Ullmann's Encyclopedia of Industrial Chemistry

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N‐Substituierte Bis‐(γ‐phenpropyl)‐amine

Cited by 4 publications

References 4 publications

Lobeline: Structure−Affinity Investigation of Nicotinic Acetylcholinergic Receptor Binding

Lobeline: Structure−Affinity Investigation of Nicotinic Acetylcholinergic Receptor Binding

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

Drugs for Functional Gastrointestinal Disorders (A03)

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