Lactone, 24. Mitt.: „γ‐Lactonisierte”︁ Neuroleptika ‐ Synthese, Stereochemie und Affinität am D<sub>2</sub>‐Rezeptor

Considering the possibility of an in vivo equilibrium 1 + 3a, the "lactonized" neuroleptic 1 is supposed to have quite different pharmakokinetic properties compared to the analogous diphenylbutylpiperidine pimocide. 1 showed little affinity to the 5-HT*-') but high (Ki = 17 nmolj) to the dopamine D*-binding site of rat striatum'). Now we want to report on the affinity of 1, its enantiomers and its ring open derivatives 3a,b to the dopamine receptors in bovine striatum, to a number of other receptors and also on the stability of 1 under various conditions.If the in vjvo formation of the hydroxy acid 3a is assumed, its affinity should be determined as well. Alkaline hydrolysis of 1 gave 3a, treatment with pyrrolidine afforded 3b, which in contrast to 3a is not easily relactonized in acidic aqueous solution or by heating. Resolution of 1 was performed via the diastereomeric salts with (+)-and (-)-dibenzoyltartaric acid to give (+)-and (-)-1. Enantiopurity (Tab. 1) was determined by HPLC on a chiralpak AD column. Tab. 1: Affinities to dopdmine D,and D2-binding sites, K, (nmol/l) ~~_ _ _~-_ _ _ _ _ _ _ _ _~ Racem. 1 (+)-I1) (-)-l*) D2 210 1050 90 750 5490 4.3I ) ee = 85% 2, ee = 97.5% ') 5tandard butaclamol a-Aminomethyllactoneshexanolides rather than pentanolidescan eliminate amines to give cytotoxic a-methylen el act one^^). To get an impression of its stability, 1 was refluxed for 3 d in solvents of increasing boiling points (ether, ethanol, toluene) and also was stirred for 3 d at 37°C in 0.1 M HCI, 0.1 M NaOH and phosphate buffer pH 7, together with one drop of tween 80. The treatment was monitored by TLC with 4-(2-oxo-1-benzimidazolinyl)piperidine, 2, and 3a as reference compounds. No formation of these or other products was observed, so 1 proved to be more stable than other a-aminola~tones~). 9 Plmoclde F Q 2 F F 3 a : R = 0 1 1 3 b : R = 0 I Arch. Phurm (Weinhelm) 326,911-912 (1493j 0 VCH Verlagsgesellschaft mbH, D-6945 1 Weinheiin, 19930365-6233/93/111 1-091 1 $5.00 + 2510

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ChemInform Abstract: Lactones. Part 24. “γ‐Lactonized” Neuroleptics. Synthesis, Stereochemistry, and Affinity at the D2 Receptor.

Lehmann

Schulze

Radwansky

1994

ChemInform

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Lactones. Part 24. "γ-Lactonized" Neuroleptics. Synthesis, Stereochemistry, and Affinity at the D2 Receptor.-Carboxylation of the lactone (I) produces the carboxylic acid (III) which is converted to the methylene lactone (V) by Mannich reaction, decarboxylation, and elimination of amine. Addition reaction of the piperidines (VI) to (V) forms the target "γ-lactonized" neuroleptics (VII). Analogously, the 3,4-disubstituted lactones (VIII) are synthesized. The affinity of the neuroleptics (VII) and (VIII) to the D2 receptor in rat brain is investigated. -(LEHMANN, J.; SCHULZE, G.; RADWANSKY, A.; Arch.

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Lactone, 24. Mitt.: „γ‐Lactonisierte”︁ Neuroleptika ‐ Synthese, Stereochemie und Affinität am D₂‐Rezeptor

Cited by 4 publications

References 7 publications

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ChemInform Abstract: Lactones. Part 24. “γ‐Lactonized” Neuroleptics. Synthesis, Stereochemistry, and Affinity at the D2 Receptor.

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Lactone, 24. Mitt.: „γ‐Lactonisierte”︁ Neuroleptika ‐ Synthese, Stereochemie und Affinität am D2‐Rezeptor

Cited by 4 publications

References 7 publications

Synthesis of Chiral 4-(ω-Hydroxyalkyl)pyrazolidin-3-ones by Ring-Chain Transformation of α-Alkylidenelactones with Hydrazines

Synthesis of Chiral 4-(ω-Hydroxyalkyl)pyrazolidin-3-ones by Ring-Chain Transformation of α-Alkylidenelactones with Hydrazines

Lactones, XXVII: “Lactonized” Pimocide ‐ Stability and Dopamine Receptor Affinity of its Enantiomers and Ring Open Derivatives

ChemInform Abstract: Lactones. Part 24. “γ‐Lactonized” Neuroleptics. Synthesis, Stereochemistry, and Affinity at the D2 Receptor.

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Product

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Lactone, 24. Mitt.: „γ‐Lactonisierte”︁ Neuroleptika ‐ Synthese, Stereochemie und Affinität am D₂‐Rezeptor