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. 2006 Feb 23;49(4):1420-32.
doi: 10.1021/jm050797a.

1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors

Peter C Meltzer  1 , David Butler, Jeffrey R Deschamps, Bertha K Madras
Affiliations

1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors

Peter C Meltzer et al. J Med Chem. .

Abstract

Dopamine, serotonin, and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research because the modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogues.

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Figures

Figure 1
Figure 1
Scheme 1
Scheme 1
General Heffe synthesis of 1-(4-substitutedphenyl)-2-pyrrolidin-1-yl-pentan-1-ones, 4ab aReagents and conditions: i) n-BuMgCl; ii) H2SO4; iii) AlCl3, Br2; iv) pyrrolidine bThe Heffe synthesis was not followed for certain compounds. Synthetic details for those compounds are presented in the Experimental Section and are discussed in the text.
Scheme 2
Scheme 2
Synthesis of Analogs 6, 7, 9f and 9ga aReagents and conditions: (i) AlCl3,Br2; (ii) Li2CO3, LiBr, DMF; (iii) pyrrolidine HCl, (HCHO)n; (iv) pyrrolidine; (v) n-BuNH2; (vi) piperidine
Scheme 3
Scheme 3
Synthesis of Compounds 9a–e
Scheme 4
Scheme 4
Resolution of 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one, 4aa aReagents: (i) Dibenzoyl-D (or L)-tartaric acid, EtOH; (ii) Recrystallization (CH2Cl2/hexanes); (iii) Na2CO3. Et2O
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