Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

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 ...

Selectivity and activation of dopamine D3R from molecular dynamics

“…In addition, we find that Tyr 7.35 , Ser 7.36 , Thr 7.39 , Tyr 7.43 , Tyr 1.39 , Val 2.61 and Glu 2.65 also contact with R-22, which is in agreement with the recent molecular docking experiments [4,14,16,18,20]. Those docking results showed that Tyr 7.35 , Ser 7.36 and Thr 7.39 in D3R represent a prominent part of the binding pocket in TM7 [4,14,18,20].…”

“…Those docking results showed that Tyr 7.35 , Ser 7.36 and Thr 7.39 in D3R represent a prominent part of the binding pocket in TM7 [4,14,18,20]. It is reported that Y7.35V mutation causes 3.9-fold decrease of ligand binding.…”

“…Imbalance of the dopaminergic system is implicated in several neurological and neuropsychiatric disorders, such as Parkinson's disease, Huntington's disease, schizophrenia, Tourette's syndrome, and drug abuse [1,[3][4][5][6][7]. All dopamine receptor subtypes belong to class A of G-protein coupled receptors [8][9][10] (GPCRs) super family, and are divided into two families [11,12] due to the basic pharmacological profiles: D 1 -like receptors including the dopamine D 1 and the D 5 receptors, are characterized by activation of adenyl acetyl cyclase mediated by stimulatory G s protein, while D 2 -like receptors consist of the dopamine D 2 , D 3 and D 4 receptors, which couple to inhibitory G i/o proteins and inhibit adenyl cyclase [13,14].…”

Synthesis of Benzo[c]azocanones and Indeno[1,2‐b]pyrroles from Oxoindanecarboxylates

“…[2] The regioisomeric benzo[c]azocan-1-one is only obtained if the activated oxime is exclusively in the (Z)-configuration. [3] Because compounds with the benzo[c]azocane motif can exhibit promising biological effects, [4] other synthetic approaches have been applied in the literature. Apart from polar C-N bond formation, such as S N , [5] S E Ar, [6] and A E reactions, [7] a 2,3-sigmatropic rearrangement of a Nbenzylammonium ylide, reported by Sommelet and Hauser, has often been used to prepare benzo[c]azocanes.…”

Novel Fused Pyrrole Heterocyclic Ring Systems as Structure Analogs of LE 300: Synthesis and Pharmacological Evaluation as Serotonin 5‐HT2A, Dopamine and Histamine H1 Receptor Ligands

“…Neuropsychiatric diseases such as schizophrenia, Parkinson's disease, or addiction are strongly related to a disregulation of the dopaminergic signal transduction [8,9]. There are five dopamine receptor subtypes that may be divided into two subfamilies: the G s -coupled D 1 -like receptors (D 1 , D 5 ) and the G i -coupled D 2 -like receptors (D 2 , D 3 , D 4 ) [10].…”