Design, Synthesis, and Melatoninergic Activity of New Azido- and Isothiocyanato-Substituted Indoles

Tsotinis, Andrew; Afroudakis, Pandelis A.; Davidson, Kathryn; Prashar, Anjali; Sugden, David

doi:10.1021/jm7010723

Cited by 30 publications

(23 citation statements)

References 48 publications

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“…To prevent ligand dissociation, irreversible ligation of electrophilic moieties like halomethylketones, isothiocyanates, Michael acceptors, or aziridinium groups of small-molecule ligands with a suitably positioned nucleophilic residue in the receptor has been used (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, irreversible ligands often suffer from incomplete cross-linking (15) and reduced receptor activation when covalent binding leads to loss of agonist efficacy (10,16).…”

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confidence: 99%

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Covalent agonists for studying G protein-coupled receptor activation

Weichert

Kruse

Manglik

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating G s -, G i -, and G q -coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β 2 -adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis. (1), and the resulting biochemical instability of the solubilized protein (2, 3). Protein crystallography, the most powerful tool for the study of GPCR structure, requires the formation of stable and conformationally homogeneous ligand-receptor complexes (4). High-affinity agonists with dissociation constants in the low to subnanomolar range and low off-rates facilitate stabilization of the protein throughout the process of expression, purification, and crystallogenesis (2); however, endogenous neurotransmitters usually show poor binding affinity. Low binding affinity with rapid association and dissociation rates leads to conformational heterogeneity that prevents the formation of diffraction-quality crystals. The rapid dissociation rate of agonists also makes it difficult to generate active-state stabilizing proteins, such as the camelid antibodies (nanobodies) that have been used to obtain active-state structures of the β 2 -adrenergic receptor (β 2 AR) (5) and M2 muscarinic receptor (6).To prevent ligand dissociation, irreversible ligation of electrophilic moieties like halomethylketones, isothiocyanates, Michael acceptors, or aziridinium groups of small-molecule ligands with a suitably positioned nucleophilic residue in the receptor has been used (7-16). However, irreversible ligands often suffer from incomplete cross-linking (15) and reduced receptor activation when covalent binding leads to loss of agonist efficacy (10, 16). Furthermore, their highly electrophilic nature and the abundance of nucleophilic groups in biological systems may lead to a low coupling selectivity (7, 8).Disulfide-based cross-linking approaches (17, 18) offer the advantage that the covalent binding of disulfide-...

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confidence: 99%

“…However, irreversible ligands often suffer from incomplete cross-linking (15) and reduced receptor activation when covalent binding leads to loss of agonist efficacy (10,16). Furthermore, their highly electrophilic nature and the abundance of nucleophilic groups in biological systems may lead to a low coupling selectivity (7,8).…”

mentioning

confidence: 99%

Covalent agonists for studying G protein-coupled receptor activation

Weichert

Kruse

Manglik

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…22,23) Subsequent reaction of 11 with commercially available arylpiperazines led to the expected displacement products 12a-h, with yields between 53% and 98%.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-hKey words indolylalkylarylpiperazine; 5-hydroxytryptamine 1A receptor; docking; binding; synthesis Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that mediates various physiological and pathological processes in the peripheral and central nervous system (CNS) by interacting with several different receptors.1-3) The 5-HT 1A receptor sub-population has attracted considerable attention in the drug discovery field.4-7) It is assumed that anxiolytic drugs such as buspirone (1), tandospirone (2), gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmacological activity through the activation of the 5-HT 1A receptor, where they act as partial agonists.8-10) The 5-HT 1A receptor is also implicated in many other physiopathological CNS processes and conditions such as neuroprotection, schizophrenia, Parkinson's and Alzheimer's diseases, acting alone or associated with other neurotransmitter receptors, especially dopamine receptors.Long-chain arylpiperazine derivatives are one of the most important classes of 5-HT 1A ligands. In general, the arylpiperazine moiety is a good template for drugs acting on many different biological targets, especially CNS receptors.11-13) As a consequence, many compounds containing this scaffold bind with high affinity at 5-HT 1A receptors, but only a few of them also show high selectivity for 5-HT 1A over other receptors. 14)Structure-activity relationship (SAR) studies, performed with numerous generations of arylpiperazine derivatives, showed that CNS activity and both, receptor affinity and selectivity depend basically on the N-1-aryl substituent and a terminal fragment bound to the N-4 atom of the piperazine moiety by an alkyl chain. In these studies, this alkyl spacer is frequently composed of two to four methylene units. 15,16) On the other hand, the indole substructure is the basic element in a large number of biologically active natural and synthetic products. In fact, until this day, the indole motif is present in more than 400 drugs and 3000 patents.17) The range of applications for these therapeutically relevant compounds includes anti-inflammatory drugs, protein kinase C inhibitors, 5-HT agonists and antagonists, melatonin agonists and glucocorticoid receptor modulators.18) Studies on structural modifications of indolylalkylarylpiperazines carried out by Heinrich et al. 14,19) reported a high-affinity pattern for 5-HT 1A agonism and succeeded in optimizing selectivity over dopamine D 2 receptors. This structural pattern considers a C5-substituted indole ring bearing different functional groups and a parasubstituted arylpiperazine. In these studies, a four-carbon atom chain was employed as a linker of both heterocyclic moieties. On the other hand, a few studies on indolylalkylarylpiperazines containing a propyl chain as a linker have been reported regarding their 5-HT 1B/1D receptor affinity. 20,21) However, the influence of a propylic connecting chain on the affinity of this type ...

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“…Probably for this reason, the effort of most laboratories has been focused upon developing melatonergic drugs for the treatment of circadian pathologies (ie, sleep disturbances or seasonal affective disorders). Thus, during the past decade, a great number of structurally different MLT receptor ligands, which range from simple indole derivatives and their bioisosteres to phenylalkyl amides, and constrained melatoninergic agents, have been reported in the literature 90–92. According to the guidelines of the International Union of Basic and Clinical Pharmacology, a selective ligand should display at least 50–100 times greater binding affinity and/or potency for one receptor subtype, relative to the other.…”

Section: Melatonergic Ligands In Developmentmentioning

confidence: 99%

Melatonergic drugs in development

Carocci¹,

Catalano²,

Sinicropi³

2014

CPAA

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Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.

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Design, Synthesis, and Melatoninergic Activity of New Azido- and Isothiocyanato-Substituted Indoles

Cited by 30 publications

References 48 publications

Covalent agonists for studying G protein-coupled receptor activation

Covalent agonists for studying G protein-coupled receptor activation

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Melatonergic drugs in development

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