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Biomedical subjects

Lee E Schechter

Publications and source records attributed to Lee E Schechter.

At least 19 recordsLinked to original sources
PubMed2006

Differentiating antidepressants of the future: efficacy and safety.

There have been significant advances in the treatment of depression since the serendipitous discovery that modulating monoaminergic neurotransmission may be a pathological underpinning of the disease. Despite these advances, particularly over the last 15years with the introduction of selective serotonin and/or norepinephrine reuptake inhibitors (SNRI), there still remain multiple unmet clinical needs that would represent substantial improvements to current treatment regimens. In terms of efficacy there have been improvements in the percentage of patients achieving remission but this can still be dramatically improved and, in fact, issues still remain with relapse. Furthermore, advances are still required in terms of improving the onset of efficacy as well as addressing the large proportion of patients who remain treatment resistant. While this is not well understood, collective research in the area suggests the disease is heterogeneous in terms of the multiple parameters related to etiology, pathology and response to pharmacological agents. In addition to efficacy further therapeutic advances will also need to address such issues as cognitive impairment, pain, sexual dysfunction, nausea and emesis, weight gain and potential cardiovascular effects. With these unmet needs in mind, the next generation of antidepressants will need to differentiate themselves from the current array of therapeutics for depression. There are multiple strategies for addressing unmet needs that are currently being investigated. These range from combination monoaminergic approaches to subtype selective agents to novel targets that include mechanisms to modulate neuropeptides and excitatory amino acids (EAA). This review will discuss the many facets of differentiation and potential strategies for the development of novel antidepressants.

Animals↗
PubMed2006

Synthesis and biological evaluation of novel compounds within a class of 3-aminochroman derivatives with dual 5-HT1A receptor and serotonin transporter affinity.

Compounds containing a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2H-1-benzopyran and a 3-alkylindole moiety linked through a common basic nitrogen were prepared and evaluated for 5-HT1A affinity, serotonin rat transporter affinity, and functional antagonist activity in vitro. 26a was found to be the most potent and selective compound in this series and was shown to possess neurochemical activity in vivo by producing acute and rapid increases in 5-HT in the rat frontal cortex.

Animals↗
PubMed2006

Alpha 2A-adrenoceptors enhance the serotonergic effects of fluoxetine.

The ability of subtype-preferring alpha(2)-adrenoceptor antagonists to enhance the neurochemical effects of the antidepressant, fluoxetine, was evaluated by in vivo microdialysis. Combining the selective alpha(2A)-adrenoceptor antagonist, BRL-44408 (10 mg/kg, s.c.), with fluoxetine (30 mg/kg, s.c.) elevated the extracellular levels of serotonin (5-HT) and noradrenaline in the rat frontal cortex, an effect not observed following antidepressant treatment alone. In contrast, combining fluoxetine with the alpha(2B)- or alpha(2C)-adrenoceptor antagonists, imiloxan (10 mg/kg, s.c.) or rauwolscine (10 mg/kg, s.c.), respectively, did not similarly alter biogenic amine levels. Collectively, these results reveal a specific role for the alpha(2A)-adrenoceptor subtype in augmenting the neurochemical effects of antidepressants.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2006

Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications.

RATIONALE: Oxytocin (OT) acts as a neuromodulator/neurotransmitter within the central nervous system (CNS) and regulates a diverse range of CNS functions. Notably, evidence from studies in females has revealed an important role for OT in regulating anxiety behavior. OBJECTIVES: The objective of this study was to examine the effects of OT on both behavioral and autonomic parameters of the anxiety response in male mice using three pharmacologically validated preclinical models of anxiety: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). RESULTS: In the FPT, both peripherally (3-30 mg/kg i.p.) and centrally (1-10 microg i.c.v.) administered OT produced dose-dependent increases in punished crossings, indicating an anxiolytic-like effect. The effects of centrally administered OT in the FPT were blocked with peripheral administration of a brain-penetrant OT receptor (OTR) antagonist WAY-162720 (30 mg/kg i.p.), and the effects of peripherally administered OT were blocked with central administration of a non-penetrant OTR antagonist L-371,257, suggesting OT acts centrally. In the EZM, centrally administered OT (0.1-1.0 microg, i.c.v.) produced significant increases in the percentage time spent in the open quadrants of the maze, comparable to alprazolam (0.5-1.0 microg, i.c.v.). In SIH, OT (1-10 mg/kg i.p.) dose-dependently attenuated stress-induced increases in core body temperature, comparable to the reference anxiolytic chlordiazepoxide (CDP) (10 mg/kg i.p.). CONCLUSIONS: These results provide specific behavioral and autonomic evidence of anxiolytic-like effects for oxytocin in males and, together with previously reported observations in females, suggest the potential utility of OTR agonism as a therapeutically relevant mechanism of action for novel anxiolytics in both sexes.

Animals↗
PubMed2006

WAY-100635 antagonist-induced plasticity of 5-HT receptors: regulatory differences between a stable cell line and an in vivo native system.

We present evidence that the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), can induce receptor internalization in a human (h)5-HT(1A) receptor Chinese hamster ovary (CHO-K1) cell system. Exposure of h5-HT(1A) CHO cells to WAY-100635 decreased the cell-surface h5-HT(1A) receptor density in a way that was both time (24-72 h) and concentration (1-100 nm) dependent.[(3)H]WAY-100635 and [(3)H]8-hydroxy-dipropylaminotetralin ([(3)H]8-OH-DPAT) saturation analyses demonstrated a significant reduction (50-60%) in total h5-HT(1A) receptor number in the WAY-100635-treated (100 nm; 72 h) compared with control cells. In WAY-100635-treated cells, the 8-OH-DPAT-mediated inhibition of forskolin (FSK)-stimulated cAMP accumulation was right-shifted and the maximal inhibitory response of 8-OH-DPAT was impaired compared with control cells. Similar results were obtained for 8-OH-DPAT-mediated Ca(2+) mobilization after WAY-100635 treatment. h5-HT(1A) receptors labeled with [(3)H]WAY-100635, as well as [(3)H]4-(2'-Methoxy)-phenyl-1-[2'-(N-2''-pyridinyl)-p-fluorobenzamido]ethyl-piperazine (MPPF), exhibited a time-dependent rate of cellular internalization that was blocked by endocytotic suppressors and was pertussis-toxin insensitive. In contrast, quantitative autoradiographic studies demonstrated that chronic treatment of rats with WAY-100635 for two weeks produced a region-specific increase in the 5-HT(1A) receptor density. In conclusion, prolonged exposure of an h5-HT(1A) cell-based system to the 5-HT(1A) antagonist, WAY-100635, induced a paradoxical internalization of cell surface receptor resulting in depressed functional activity. This suggests that an antagonist can influence 5-HT(1A) receptor recycling in vitro differently to in vivo regulatory conditions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists.

Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6 receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8-13) appear to be able to adopt a conformation that allows high affinity 5-HT6 receptor binding, while the beta-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).

Adenylyl Cyclases↗
PubMed2005

Synthesis and biological evaluation of benzodioxanylpiperazine derivatives as potent serotonin 5-HT(1A) antagonists: the discovery of Lecozotan.

A series of benzodioxanylpiperazine derivatives possessing a 4-aryl amide substituent was prepared and evaluated for 5-HT(1A) affinity and functional antagonist activity in vitro and in vivo. All of the compounds in this series possessed high affinity for the human 5-HT(1A) receptor and many displayed potent antagonist activity in vitro and varying degrees of intrinsic activity in vivo. Compound 11c (Lecozotan) was selected for further development and is currently in clinical trials.

Animals↗
PubMed2005

4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands.

The preparation of a novel class of 4-(2-aminoethoxy)-N-(phenylsulfonyl)indoles which exhibit high affinity towards the 5-HT6 receptor is reported here. Among these compounds, 4-(2-methylaminoethoxy)-N-(phenylsulfonyl)indole 5g showed superior affinity (Ki = 1 nM) towards the 5-HT6 receptor as well as excellent selectivity (> 2000-fold) against the closely related subtype 5-HT7 receptor.

Binding, Competitive↗
PubMed2005

Studies towards the next generation of antidepressants. Part 4: derivatives of 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine with affinity for the serotonin transporter and the 5-HT1A receptor.

Derivatives of the serotonin reuptake inhibitor 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine, in which serotonin 1A (5-HT(1A)) receptor pharmacophoric elements are incorporated, are reported. Analogs exhibiting affinity for both the serotonin transporter and the 5-HT(1A) receptor are described. Compounds containing 1-(4-indolyl)piperazine and 2-(1H-indol-4-yloxy)ethylamine are promising leads for further SAR studies.

Antidepressive Agents↗
PubMed2005

N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor antagonists.

A series of N(1)-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)indole derivatives was designed and synthesized. These compounds were shown to have high affinity for the 5-HT(6) receptor. Two analogs, 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-1-sulfonyl]-phenylamine 15g and 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole-1-sulfonyl]-phenylamine 15y, had 0.4 and 3.0 nM affinity, respectively, and antagonized the production of adenylate cyclase at sub-nanomolar concentrations.

Adenylyl Cyclases↗
PubMed2005

Innovative approaches for the development of antidepressant drugs: current and future strategies.

Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, alpha-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT2C, 5-HT6) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.

Animals↗
PubMed2005

Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs.

The birth of new neurons, or neurogenesis, in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans. A major finding in the field of depression is that treatment with antidepressant drugs increases hippocampal neurogenesis. This review presents a current summary of this field of study and presents the hypothesis that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs. It has been demonstrated that multiple classes of antidepressant drugs increase hippocampal cell proliferation and neurogenesis in a chronic and not acute time course, which corresponds to the therapeutic time course necessary for effects. Conversely, animal models of depression or stress paradigms decrease cell proliferation. Clinically, there is evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders. Taken together, this data indicates that reduced hippocampal cell number may be involved in the pathophysiology of depression and reversal of this may be one way the antidepressant drugs exert their effects. We hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors. In addition, the ability of novel compounds to be tested for the neurogenic potential may become an additional way to evaluate a compound for putative antidepressant effects.

Animals↗
PubMed2004

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands.

Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which N,N-dimethyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8t and N-methyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8u showed high affinity for 5-HT(6) receptors with K(i)=3.7 and 5.7 nM, respectively.

Amines↗
PubMed2004

Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity.

Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds 11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT(1A) affinity. Moreover, several of these compounds possess functional 5-HT(1A) antagonism. Optimal compounds are, 4-indolyloxyethane 21, 4-indolyloxypropanes 25, and 27, which possess potent 5-HT-T affinity (5-HT-T K(i): 21: 1.2nM, 25: 0.54nM, 27: 0.38nM) and good 5-HT(1A) affinity/antagonism (5-HT(1A)K(i), [(35)S]GTPgammaS: E(max) (%): 21: 111.1nM, 0%; 25: 173.2nM, 0%; 27: 107nM, 0%).

Animals↗
PubMed2004

Regulators of G-protein signaling 4: modulation of 5-HT1A-mediated neurotransmitter release in vivo.

Regulators of G-protein signaling (RGS) play a key role in the signal transduction of G-protein-coupled receptors (GPCRs). Specifically, RGS proteins function as GTPase accelerating proteins (GAPs) to dampen or "negatively regulate" GPCR-mediated signaling. Our group recently showed that RGS4 effectively GAPs Galpha(i)-mediated signaling in CHO cells expressing the serotonin-1A (5-HT(1A)) receptor. However, whether a similar relationship exists in vivo has yet to be identified. In present studies, a replication-deficient herpes simplex virus (HSV) was used to elevate RGS4 mRNA in the rat dorsal raphe nuclei (DRN) while extracellular levels of 5-HT in the striatum were monitored by in vivo microdialysis. Initial experiments conducted with noninfected rats showed that acute administration of 8-OH-DPAT (0.01-0.3 mg/kg, subcutaneous [s.c.]) dose dependently decreased striatal levels of 5-HT, an effect postulated to result from activation of somatodendritic 5-HT(1A) autoreceptors in the DRN. In control rats receiving a single intra-DRN infusion of HSV-LacZ, 8-OH-DPAT (0.03 mg/kg, s.c.) decreased 5-HT levels to an extent similar to that observed in noninfected animals. Conversely, rats infected with HSV-RGS4 in the DRN showed a blunted neurochemical response to 8-OH-DPAT (0.03 mg/kg, s.c.); however, increasing the dose to 0.3 mg/kg reversed this effect. Together, these findings represent the first in vivo evidence demonstrating that RGS4 functions to GAP Galpha(i)-coupled receptors and suggest that drug discovery efforts targeting RGS proteins may represent a novel mechanism to manipulate 5-HT(1A)-mediated neurotransmitter release.

8-Hydroxy-2-(di-n-propylamino)tetralin↗