A series of 52 conformationally constrained butyrophenones have been synthesized and pharmacologically tested as antagonists at 5-HT2A, 5-HT2B, and 5-HT2C serotonin receptors, useful for dissecting the role of each 5-HT2 subtype in pathophysiology. These compounds were also a consistent set for the identification of structural features relevant to receptor recognition and subtype discrimination. Six compounds were found highly active (pK i > 8.76) and selective at the 5-HT2A receptor vs 5-HT2B and/or 5-HT2C receptors. Piperidine fragments confer high affinity at the 5-HT2A receptor subtype, with benzofuranone- and thiotetralonepiperidine as the most selective derivatives over 5-HT2C and 5-HT2B receptors, respectively; K i  2A/2C and/or K B  2A/2B ratios greater than 100 were obtained. Compounds showing a more pronounced selectivity at 5-HT2A/5-HT2C than at 5-HT2A/5-HT2B bear 6-fluorobenzisoxazolyl- and p-fluorobenzoylpiperidine moieties containing one methylene bridging the basic piperidine to the alkanone moiety. An ethylene bridge between the alkanone and the amino moieties led to ligands with higher affinities for the 5-HT2B receptor. Significant selectivity at the 5-HT2B receptor vs 5-HT2C was observed with 1-1[(1-oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl]-4-[3-(p-fluorobenzoyl)propyl]piperazine (more than 100-fold higher). Although piperidine fragments also confer higher affinity at 5-HT2C receptors, only piperazine-containing ligands were selective over 5-HT2A. Moderate selectivity was observed at 5-HT2C vs 5-HT2B (10-fold) with some compounds bearing a 4-[3-(6-fluorobenzisoxazolyl)]piperidine moiety in its structure. Molecular determinants for antagonists acting at 5-HT2A receptors were identified by 3D-QSAR (GRID-GOLPE) studies. Docking simulations at 5-HT2A and 5-HT2C receptors suggest a binding site for the studied type of antagonists (between transmembrane helices 2, 3, and 7) different to that of the natural agonist serotonin (between 3, 5, and 6).

No abstract

Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained aminobutyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), and evaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics. The cinnoline derivative 23 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2C compared to both the 5-HT2A and D2 receptors.

A series of novel conformationally restricted butyrophenones (2-(aminoethyl)- and 3-(aminomethyl)thieno- or benzocycloalkanones bearing (6-fluorobenzisoxazolyl)piperidine, (p-fluorobenzoyl)piperidine, (o-methoxyphenyl)piperazine, or linear butyrophenone fragments) were prepared and evaluated as atypical antipsychotic agents by in vitro assays of affinity for dopamine receptors (D(1), D(2)) and serotonin receptors (5-HT(2A), 5-HT(2C)) and by in vivo assays of antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cycloalkanone structure. As a group, compounds with a benzisoxazolyl fragment had the highest 5-HT(2A) activities, followed by the benzoylpiperidine derivatives; in general, alpha-substituted cycloalkanone derivatives were more active than the corresponding beta-substituted congeners. CoMFA (comparative molecular field analysis) and docking studies showed electrostatic, steric, and lipophilic determinants of 5-HT(2A) and D(2) affinities and 5-HT(2A)/D(2) selectivity. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4H-5, 6-dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisox azol-3 -yl)piperidine (23b, QF 0510B), N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (24b, QF 0610B), and N-[(7-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-6-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (29b, QF 0902B) suggest that they may be effective antipsychotic drugs with low propensity to induce extrapyramidal side effects.

No abstract

No abstract

No abstract

a b s t r a c tA series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D 1 , D 2 , and D 3 receptors. Some of these compounds showed high D 2 and/or D 3 affinity and selectivity over the D 1 receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D 2 and D 3 affinities. Structural models of the complexes between some of the most representative compounds of this series and the D 2 and D 3 receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT 2A which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics.Ó 2009 Elsevier Ltd. All rights reserved.Dopamine (DA) is a major neurotransmitter in the central nervous system (CNS) that plays important roles in behaviour and cognition, ranging from movement to emotion, sensitization to addiction, and development to plasticity. All DA receptors belong to a superfamily of large peptides that are coupled to G-proteins and modified by attached carbohydrate, lipid-ester or phosphate groups. They are characterized by having seven hydrophobic transmembrane-spanning regions, as well as a functionally critical third intracytoplasmic loop that interacts with G-proteins and other effector molecules to mediate the physiological and neurochemical effects of the receptors. Based on their pharmacological profiles, including their effects on different signal transduction cascades, these receptors are currently divided into two families: the D 1 -like family or adenylyl-cyclase stimulators, which includes D 1 and D 5 receptors, and the D 2 -like family or adenylyl-cyclase inhibitors, which includes D 2 , D 3 and D 4 receptors. 1 The D 3 dopamine receptor was first identified and clonated by Sokoloff et al. 2 in 1990 and has been shown to be an interesting target for different CNS diseases. Although its structure and pharmacology are very similar to dopamine D 2 , the D 3 receptor is generally less abundant than the D 2 receptor, and the difference is particularly striking in the caudate putamen, where D 2 receptors are densest and D 3 receptors are poorly represented. 3 Moreover, D 3 -binding sites and mRNA encoding D 3 receptors are concentrated in the limbic brain areas known to be associated with cognitive and emotional functions. 4 Due to this, the D 3 receptor has been suggested to be a potential target in the treatment of neurological disorders such as schizophrenia, and drug abuse. 5 In schizophrenia, a blockade of D 2 receptors has been considered to be the main mechanism responsible for the efficacy of antipsychotics, 6 but the complex profiles of some atypical drugs challenged this assumption, that is, clozapine exhibits activity at multiple receptors. 7 Now there is an increasing body of clinical evidence that supports the notion that multi-target ligands may be more efficacious than strictly selective ...