1,721,147 research outputs found
Editorial
No full textSerotonin (5-HT) is a widely distributed neurotransmitter and hormone in the mammalian central nervous system and
periphery. In 1957 Gaddum and Picarelli reported the characterization of two distinct receptors for serotonin, namely M and D
receptors. Since then, several other serotonin receptors have been identified and characterized. Starting from 1988, with the
advent of molecular cloning techniques, fourteen receptors of serotonin have been cloned from several species.
After nearly fifty years of intense research efforts, witnessed by the introduction into the market of serotonergic drugs such
as buspirone, ondansetron, ketanserine, and paroxetine among many others, one could ask whether it is still worth studying the
serotonin system. Clearly, the answer is yes.
From a search of Scifinder® database on July 2005, it emerged that among the 5-HT receptors, the 5-HT2C subtype was the
object of intense research. Drs. G. Di Giovanni, V. Di Matteo, M. Pierucci, A. Benigno and E. Esposito present a review on the
pharmacological characteristics of this receptor, whereas Drs. E. Lacivita and M. Leopoldo offer an overview on the studies
carried out in both pharmaceutical companies and academy aimed to the identification of selective agents for 5-HT2C receptor.
The review by Drs. M. J. Bubar and K. A. Cunningham focus on one of the most promising therapeutic application for 5-HT2C
and 5-HT2A receptor agents, namely the treatment of psychostimulant addiction in humans.
The role of 5-HT in pain mechanisms has been evidence nearly twenty years ago. Recently, several 5-HT receptor subtypes
have been localized into the spinal cord. These new findings have supported the involvement of serotonin receptors in pain
mechanisms. Dr. J. A. Lopez-Garcia has reviewed electrophysiological observations from spinal neurons using local
administration of serotonergic agents. The review by Drs. J. A. Mico, E. Berrocoso, A. Ortega-Alvaro, J. Gibert-Rahola, and M.
O. Rojas-Corrales focuses on 5-HT1A receptors as a target in the search of new pharmacological approaches in the
augmentation of analgesia.
The 5-HT3 receptor has been the target for the develovepment of several drugs for chemotherapy induced emesis therapy.
Starting from the clinical use of such agents some other potential therapeutic uses for 5-HT3 receptor antagonist have emerged.
Drs. W. Müller, B. L. Fiebich, and T. Stratz have reviewed their physiology–driven studies on new treatment options in
rheumatic diseases using 5-HT3 receptor antagonists.
The last two reviews are important updates on studies performed in the field of serotonergic agents. In particular, the review
by Dr. A. Bojarski provide a detailed overview on the pharmacophore models proposed up-to-date for the serotonergic
receptors. The review by A. M. Moresco, M. Materrese, and F. Fazio describes the state of the art in the discovery of PET and
SPET radioligands for the in vivo visualization of serotonin receptors
Serotonin7 Receptors (5-HT7Rs) and their Ligands
No full textAbstract: Serotonin (5-HT) is involved in various physiological and pathological
processes by interaction with 14 distinct receptor subtypes, grouped in seven classes of
receptors (5-HT1-7) on the basis of amino acid sequence, pharmacology, and signal
transduction pathways. The 5-HT7R is a G-protein coupled receptor with seven
transmembrane domains. It was found by the application of molecular cloning and has
been identified in rat, mouse, human, pig, and guinea pig. Although the biological
functions of the 5-HT7Rs are poorly understood, preliminary evidence suggests that it
may be involved in depression, control of circadian rhythms, and relaxation of vascular
smooth muscles. For these reasons, the 5-HT7R has become a target for the development of novel drugs. This
review will give a brief introduction of the pharmacology of 5-HT7R (molecular structure, distribution of 5-
HT7R mRNA, localization of the 5-HT7R protein, functional correlates, and therapeutic potential) and a detailed
survey of the 5-HT7R ligands, which have appeared in the literature in both papers and patents. Structureactivity
relationships (SAR) of these ligands will also be described
N-[omega-[4-(2-Methoxyphenyl)-1-piperazinyl]alkyl]-2-quinolinamines as High-Affinity Fluorescent 5-HT1A Receptor Ligands
No full textWe here report on the design, synthesis, binding affinities, and fluorescent properties of a series of serotonin 5-HT 1A receptor ligands, with N-[omega-[4-(2-methoxyphenyl)-1-piperazinyl]alkyl]-2-quinolinamine structure. Several of the new ligands displayed nanomolar affinity at 5-HT 1A receptor and good fluorescent properties. In particular, derivative 24 showed a favorable combination of 5-HT 1A receptor affinity ( K i = 0.4 nM), Stokes shift (excitation wavelength = 381 nm, emission wavelength = 455 nm), and quantum yield in ethanol (Phi = 0.45)
Selective Agents for Serotonin2C (5-HT2C) Receptor
No full textThe serotonin2C (5-HT2C) receptor has attracted a lot of attention owing to its role in appetite regulation,
depression, obsessive-compulsive disorder (OCD), panic disorders, and substance abuse. This review summarizes nonpatent
and patent literature up to November 2005 that deals with the synthesis and characterization of selective 5-HT2C
receptor agonists and antagonists. Highlights on structure-activity relationships have been included, when possible
The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat
No full textThe effects of LP-44, a selective 5-HT7 receptor agonist, and of SB-269970, a selective 5-HT7 receptor
antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The
5-HT7 receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light
period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25–5.0mM)into theDRNinduced a significant
reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were
observed after the direct administration into the DRN of SB-269970 (0.5–1.0 mM). Pretreatment with a
dose of SB-269970 (0.5mM) that significantly affects sleep variables antagonized the LP-44 (2.5mM)-
induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of
REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic
neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and
pedunculopontine tegmental nuclei involved in the promotion of REMS
Systemic administration and local microinjection into the central nervous system of the 5-HT(7) receptor agonist LP-211 modify the sleep-wake cycle in the rat.
No full textN-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand
No full textIncrease of Capsaicin-Induced Trigeminal Fos-Like Immunoreactivity by 5-HT(7) Receptors.
No full textOBJECTIVE:
To explore whether pharmacological stimulation of the 5-hydroxytryptamine(7) (5-HT(7) ) receptor modulates Fos-like immunoreactivity in the trigeminal nucleus caudalis of rats.
BACKGROUND:
The serotonin 5-HT(7) receptor was proposed to be involved in migraine pathogenesis and evidence suggests it plays a role in peripheral nociception and hyperalgesia through an action on sensory afferent neurons.
METHODS:
The potential activating or sensitizing role of 5-HT(7) receptors on trigeminal sensory neurons, as visualized by Fos-like immunoreactivity in the superficial layers of the trigeminal nucleus caudalis in rats, was investigated using the 5-HT(7) receptor agonist, LP-211, in the absence and the presence of intracisternal capsaicin, respectively. The agonist effect was characterized with the 5-HT(7) receptor antagonist, SB-656104. Male Wistar rats received a subcutaneous injection of LP-211, SB-656104, and SB-656104 + LP-211. They were then anesthetized and prepared to receive an intracisternal injection of capsaicin or its vehicle. Animals were perfused and brains removed; sections of the brain stem from the area postrema to the CI level were obtained and processed for Fos immunohistochemistry.
RESULTS:
Capsaicin but not its vehicle induced Fos-like immunoreactivity within laminae I and II of trigeminal nucleus caudalis. Pretreatment with LP-211 had no effect on Fos-like immunoreactivity but strongly increased the response produced by capsaicin; this effect was abolished by SB-656104. Interestingly, capsaicin-induced Fos-like immunoreactivity was abolished by SB-656104 pretreatment thus suggesting involvement of endogenous 5-HT.
CONCLUSIONS:
Data suggest that 5-HT(7) receptors increase activation of meningeal trigeminovascular afferents and/or transmission of nociceptive information in the brain stem. This mechanism could be relevant in migraine and its prophylactic treatment
5 HT1A receptor, an old target for new therapeutic agents
No full textThe serotonin receptor subtype 5-HT1A was one of the first serotonin receptor subtypes pharmacologically
characterized. Over the last twenty years the 5-HT1A receptor has been the object of intense research efforts as witnessed
by the 5-HT1A acting drugs marketed as anxiolytics. In recent years, several new chemical entities targeting the 5-HT1A
receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic indications
(neuroprotection, cognitive impairment, Parkinson Disease and related disorders, pain treatment). The present review will
focus on those 5-HT1A receptor agents that entered preclinical trials starting from 2000
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