- Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and σ receptors
-
The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and σ S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2 and D3 receptors compared to haloperidol, although they still possess affinities in the 100-200-nM range. Both enantiomers of 3a possess potent and equal affinity for S1 sites (K(i): 1-2 nM), only slightly weaker than haloperidol (K(i): 0.33 nM). At S2 sites, (R)-(+)-3a displays similar affinity to haloperidol (K(i): 31 and 26 nM, respectively), while (S)-(-)-3a is slight more potent (K(i): 8.2 nM). The stereoselectivity profile of the enantiomers of 3b at D2 and D3 receptors is quite similar to that of 3a, (S)-(-)-3b being about 4 times more potent than its enantiomer at both receptors. (R)-(+)-3b binds preferentially to σ S1 over S2 sites, while (S)-(-)-3b displays the opposite selectivity profile. Both enantiomers of 3c possess very weak affinity for D2 and D3 receptors. In a manner similar to the enantiomers of 3b, the affinity of (R)-(+)-3c is greater for S1 than S2 sites, while (S)-(-)-3c displays the opposite selectivity profile. Following parenteral administration of both enantiomers of 3a, dopamine synthesis and turnover in rat striatum, cortex, and mesolimbic areas were increased, in a manner similar to the effects produced by haloperidol itself. Additional studies will be required to assess with certainty whether the effects were due to the compounds themselves or simply were a consequence of the in vivo oxidation to haloperidol.
- Jaen,Caprathe,Pugsley,Wise,Akunne
-
-
Read Online
- Mn-Enabled Radical-Based Alkyl-Alkyl Cross-Coupling Reaction from 4-Alkyl-1,4-dihydropyridines
-
Highly efficient alkylation of β-chloro ketones and their derivatives was achieved by means of domino dehydrochlorination/Mn-enabled radical-based alkyl-alkyl cross-coupling reaction. In situ-generated α,β-unsaturated ketones and their analogues were identified as the reaction intermediates. Known bioactive compounds, such as melperone and azaperone, could be easily prepared from β-chloropropiophenone in two steps.
- Wang, Jie,Pang, Yu-Bo,Tao, Na,Zeng, Run-Sheng,Zhao, Yingsheng
-
p. 15315 - 15322
(2019/11/19)
-
- 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction
-
A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2- ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D 4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
- Kolasa, Teodozyj,Matulenko, Mark A.,Hakeem, Ahmed A.,Patel, Meena V.,Mortell, Kathleen,Bhatia, Pramila,Henry, Rodger,Nakane, Masaki,Hsieh, Gin C.,Terranova, Marc A.,Uchic, Marie E.,Miller, Loan N.,Chang, Renje,Donnelly-Roberts, Diana L.,Namovic, Marian T.,Hollingsworth, Peter R.,Martino, Brenda,El Kouhen, Odile,Marsh, Kennan C.,Wetter, Jill M.,Moreland, Robert B.,Brioni, Jorge D.,Stewart, Andrew O.
-
p. 5093 - 5109
(2007/10/03)
-