Derivatives as 5HT1A Receptor Ligands-Past and Present

Caliendo, Giuseppe; Santagada, Vincenzo; Perissutti, Elisa; Fiorino, Ferdinando

doi:10.2174/0929867054367220

Cited by 81 publications

(81 citation statements)

References 112 publications

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“…The unsubstituted indolepropylphenylpiperazine (12a) showed a marked affinity for 5-HT 1A , which increased after the introduction of a methoxyl group in the ortho position (12b). This result agrees with a number of previous studies 11,14,[24][25][26] in which the 2-methoxyarylpiperazine derivative exhibited one of the highest affinities of the series.…”

Section: Resultssupporting

confidence: 93%

“…In general, the arylpiperazine moiety is a good template for drugs acting on many different biological targets, especially CNS receptors. [11][12][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.…”

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confidence: 99%

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Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-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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Section: Resultssupporting

confidence: 93%

mentioning

confidence: 99%

Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…However, it could not be ruled out that subtle changes, beyond the detection limit of in vivo microdialysis coupled to HPLC detection could occur. Among the 14 subtypes of 5-HT receptors, the 5HT 2A and 5-HT 1A subtypes have been consistently found to be involved in mood regulation (Caliendo et al, 2005;Weisstaub et al, 2006). As shown in supplemental Figure S1 (available at www.jneurosci.org as supplemental material), 5-HT 2A binding sites in limbic areas and in the raphe are not altered following VGLUT3 deletion.…”

Section: Vglut3mentioning

confidence: 94%

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

Amilhon¹,

Lepicard²,

Renoir³

et al. 2010

J. Neurosci.

159

192

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Three different subtypes of Hϩ -dependent carriers (named VGLUT1-3) concentrate glutamate into synaptic vesicles before its exocytotic release. Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGLUT3. It was recently reported that VGLUT3 increases acetylcholine vesicular filling, thereby, stimulating cholinergic transmission. This new regulatory mechanism is herein designated as vesicular-filling synergy (or vesicular synergy). In the present report, we found that deletion of VGLUT3 increased several anxiety-related behaviors in adult and in newborn mice as early as 8 d after birth. This precocious involvement of a vesicular glutamate transporter in anxiety led us to examine the underlying functional implications of VGLUT3 in 5-HT neurons. On one hand, VGLUT3 deletion caused a significant decrease of 5-HT 1A -mediated neurotransmission in raphe nuclei. On the other hand, VGLUT3 positively modulated 5-HT transmission of a specific subset of 5-HT terminals from the hippocampus and the cerebral cortex. VGLUT3-and VMAT2-positive serotonergic fibers show little or no 5-HT reuptake transporter. These results unravel the existence of a novel subset of 5-HT terminals in limbic areas that might play a crucial role in anxiety-like behaviors. In summary, VGLUT3 accelerates 5-HT transmission at the level of specific 5-HT terminals and can exert an inhibitory control at the raphe level. Furthermore, our results suggest that the loss of VGLUT3 expression leads to anxiety-associated behaviors and should be considered as a potential new target for the treatment of this disorder.

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“…A total of 259 5-HT 1A receptor ligands were collected from previous studies [1, , which are composed of 137 agonists and 122 antagonists with diverse structural classes such as aminotetralins, indolylalkylamines, ergolines, aporphines, arylpiperazines and aryloxyalkylamines (Tables S1 and S2 in Supplementary Information). Because we aimed to build a binary classifier, the partial agonists of the 5-HT 1A receptor were classified as agonists.…”

Section: Data Setsmentioning

confidence: 99%