Über die Mutarotation des Lobelins. <i>Cis‐trans</i>‐Isomere in der Reihe der <i>Lobelia</i>‐Alkaloide. 9. Mitteilung über Alkaloidsynthesen

Ebnöther, A.

doi:10.1002/hlca.660410210

Cited by 20 publications

(11 citation statements)

References 6 publications

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“…Compound 5a: mp 149-150 °C (lit. 31 N-Methyl-2,6-cis-bis(2-phenethyl)piperidine (6a)-Compound 5a (420 mg, 1.38 mmol) was dissolved in methanol (50 mL) and 10% Pd/C (40 mg) was added. The mixture was hydrogenated on a Parr hydrogenation apparatus (45 psi) for 18 h. The catalyst was removed by filtration through a Celite pad.…”

Section: Experimental Section Chemistrymentioning

confidence: 99%

“…The crude product was purified by silica gel column chromatography (21) was prepared according to a reported method. 31 Utilizing a similar procedure to that described for the preparation of 5a and 5b from lobeline (1a/1b), compounds 22a (18%) and 22b (13%) were obtained in pure form from norlobelanine (21). N-Methyl-2,6-cis-bis(1-naphthalenethyl)piperidine(28b)-NaBH 3 CN (344 mg, 5.50 mmol) was added to a mixture of 28a (434 mg, 1.10 mmol), paraformaldehyde (330 mg, 11.00 mmol), and methanol (10 mL).…”

Section: Experimental Section Chemistrymentioning

confidence: 99%

“…C-2 epimerization of lobeline ( 1a ) in K 2 CO 3 /methanol for 48 h at room temperature afforded an equal mixture of the two C-2 epimers, 1a and 1b , , which were transformed into compound 7 via reduction with NaBH 4 in absolute ethanol. Utilizing previously described dehydration methodologies, , compound 7 was treated with 85% phosphoric acid to yield a mixture of the cis - and trans -distyryl compounds 5a 31 (MTD) and 5b 31 ((−)-TTD), which were obtained in their pure isomeric forms via silica gel column chromatographic separation. Catalytic hydrogenation of 5a afforded lobelane ( 6a ), , and similar treatment of 5b afforded (−)-2 S ,6 S trans -lobelane [(−)- trans -lobelane, 6b ].…”

Section: Chemistrymentioning

confidence: 99%

“…The preparation of compound 22a , the N -demethylated analogue of MTD ( 5a ), is illustrated in Scheme . A mixture of cis- and trans- norlobelanine ( 21 ) was prepared . Utilizing a similar procedure for the preparation of 5a and 5b from the mixture of lobeline isomers 1a and 1b , the meso-compound 22a was prepared from 21 and obtained in an isomerically pure form; the racemic compound 22b/c was also isolated from this reaction.…”

Section: Chemistrymentioning

confidence: 99%

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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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Section: Experimental Section Chemistrymentioning

confidence: 99%

Section: Experimental Section Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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

et al. 2005

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“…Compound 18 was prepared by dehydration of (-)lobeline under acidic conditions using the literature method described for the dehydration of (+)lobeline. 24 Catalytic reduction of 18 afforded 16; the hydroxyl analogue 16 was oxidized in the presence of pyridinium dichromate to ketone 15. The styryl analogue 19 was obtained by Clemmensen reduction of (-)lobeline, by taking advantage of a previous report that Clemmensen reduction of benzylic ketones gives alkenes as the product.…”

Section: Chemistrymentioning

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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Sedum‐Alkaloide, III. Zur Konstitution des Sedinins

Franck

1959

Chem. Ber.

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Das tertiare Alkaloid Sedinin C17HzsN02 aus Sedum ucre L. enthat zwei Hydroxylgruppen, eine N-Methylgruppe und einen Phenylrest und gibt bei der Kaliumpermanganatoxydation Essigsiiure und BenzoesBure. Es wurde katalytisch zu einem kristallisierten Dihydrosedinin hydriert, das nach selektiver Chromsaureoxydation 8-Methyl-10-phenyl-lobelidion ergab, welches unter Beriicksichtigung der sterischen Isomeriem6glichkeiten mit der synthetisch dargestellten Verbindung identiliziert werden komte. Danach ist Sedinin ein 8-~fethyl-lO-phenyl-dehydro-lobelidiol. Dihydrosedinin untencheidet sich vom (+)-8-Methyl-lO-phenyl-lobelidiol, das S C H~P F und Mitarbb. kurzlich aus Lobeliu inguru isolierten, nur in der Konfiguration.Bei der systematischen Untersuchung der biogenetisch und medizinisch interessanten Alkaloide aus Sedum ucre L. (Fam. Crassuluceue) fanden wir vier Haupt-und sechs Nebenalkaloide. Unter den in kristallisierter Form isolierten Alkaloiden waren a u k r Seduminz) und Sedridid) zwei neue Basen hoheren Molekulargewichts, C*,HzsN021), deren ehe mit dem von C. SCH~PF und R. UNGER4) aus derselben Pflanze isolierten Sedinin identisch ist. Das zweite neue Alkaloid, das Sedinon, ist in geringerer Menge in der Pflanze enthalten. Tab. 1 zeigt die aus Sedum ucre erhaltenen Ausbeuten an schrnelzpunktreinen Alkaloiden.

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Über die Mutarotation des Lobelins. Cis‐trans‐Isomere in der Reihe der Lobelia‐Alkaloide. 9. Mitteilung über Alkaloidsynthesen

Abstract: Die Mutarotation des Lobelins beruht auf einer Racemisierung an dem Ringkohlenstoffatom, das die Phenacylgruppe trägt. Es wird gefunden, dass sich Verbindungen, die in α‐Stellung am Piperidinring eine Phenacylgruppe tragen, leicht umlagern.

Cited by 20 publications

References 6 publications

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

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

Lobeline: Structure−Affinity Investigation of Nicotinic Acetylcholinergic Receptor Binding

Sedum‐Alkaloide, III. Zur Konstitution des Sedinins

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