Novel N-Substituted Indol-3-ylglyoxylamides Probing the LDiand L1/L2Lipophilic Regions of the Benzodiazepine Receptor Site in Search for Subtype-Selective Ligands†

2007 ◽  
Vol 50 (7) ◽  
pp. 1627-1634 ◽  
Author(s):  
Giampaolo Primofiore ◽  
Sabrina Taliani ◽  
Federico Da Settimo ◽  
Anna Maria Marini ◽  
Concettina La Motta ◽  
...  
Keyword(s):  
Receptor Site ◽  
Benzodiazepine Receptor ◽  
Selective Ligands ◽  
Subtype Selective

scholarly journals A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

2015 ◽  
Vol 2015 ◽  
pp. 1-54 ◽  
Author(s):  
Terry Clayton ◽  
Michael M. Poe ◽  
Sundari Rallapalli ◽  
Poonam Biawat ◽  
Miroslav M. Savić ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Benzodiazepine Receptor ◽  
Binding Pocket ◽  
Positive Allosteric Modulator ◽  
Gaba A ◽  
Behavioral Studies ◽  
Selective Ligands ◽  
Recent Developments ◽  
Molecular Modeling Studies ◽  
Subtype Selective

An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.

Differential α2A- and α2C-adrenoceptor protein expression in presynaptic and postsynaptic density fractions of postmortem human prefrontal cortex

2018 ◽  
Vol 33 (2) ◽  
pp. 244-249 ◽  
Author(s):  
Amaia M Erdozain ◽  
Iria Brocos-Mosquera ◽  
Ane M Gabilondo ◽  
J Javier Meana ◽  
Luis F Callado
Keyword(s):  
Prefrontal Cortex ◽  
Protein Expression ◽  
Therapeutic Potential ◽  
Postsynaptic Density ◽  
Subcellular Fractionation ◽  
Similar Distribution ◽  
Density Fractions ◽  
Physiological Relevance ◽  
Selective Ligands ◽  
Subtype Selective

Background: Three different α2-adrenoceptor (α2-AR) subtypes have been described. The α2A-AR and α2C-AR subtypes are highly expressed in the human prefrontal cortex, where they modulate neurotransmission. However, due to the lack of subtype-selective ligands, the physiological relevance of both subtypes has not been fully resolved. Aims: In this context, the aim of the present study was to characterize the protein expression of both α2-AR subtypes, in different synaptic fractions of postmortem human prefrontal cortex. Methods: A subcellular fractionation of the samples was performed and the protein expression of α2A- and α2C-ARs was measured in presynaptic membranes and postsynaptic density fractions by Western blot. Results: The results revealed that the α2A-AR subtype is mainly located postsynaptically (95±3%) whereas the remaining 5±3% is in the presynapse. Conversely, the α2C-AR subtype showed a similar distribution between pre- and postsynaptic membranes, with a slightly higher percentage present in the presynapse (60±2% vs. 40±2%). Conclusions: These findings could explain some contradictory effects reported for α2-AR agonists and antagonists in the human prefrontal cortex. Furthermore, the present data could contribute to elucidating the therapeutic potential of selectively targeting α2A- or α2C-AR subtypes.

Both CCK-A and CCK-B/gastrin receptors are present on rabbit vagus nerve

1992 ◽  
Vol 263 (3) ◽  
pp. R591-R595 ◽  
Author(s):  
C. W. Lin ◽  
T. R. Miller
Keyword(s):  
Vagus Nerve ◽  
Receptor Site ◽  
Vagal Afferents ◽  
Scatchard Analysis ◽  
Vagus Nerves ◽  
Binding Studies ◽  
Cck Receptors ◽  
High Affinity ◽  
Selective Agonists ◽  
Subtype Selective

Cholecystokinin (CCK) receptors on vagal afferents have been implicated in many of the actions of the brain-gut peptide CCK, including satiety. Autoradiographic studies in rats have demonstrated the presence of CCK-A-type receptors on vagus nerves. However, direct and detailed characterization of this important CCK receptor site has never been reported with membrane-binding techniques. Using 125I-Bolt-on-Hunter-CCK octapeptide (125I-BH-CCK-8) and the recently discovered selective agonists and antagonists of CCK receptors, we have delineated the properties of CCK receptors on rabbit vagus nerve. 125I-BH-CCK-8 binding sites appeared to be homogeneous by the Scatchard analysis, with a dissociation constant of 0.14 nM and a maximum binding of 72 fmol/mg protein. However, competition studies using selective CCK ligands showed that the vagal CCK receptors are heterogeneous. A71378, a selective CCK-A agonist, showed biphasic displacement curves, with the high-affinity portion (less than 10 nM) accounting for approximately 60% and the low-affinity portion for approximately 40%. Competitive binding studies using A63387, a selective CCK-B/gastrin receptor agonist, also showed biphasic displacement curves, with the high-affinity portion (less than 30 nM) at approximately 40% and the low-affinity portion at approximately 60%. Under conditions which selectively examined vagal CCK-A or CCK-B/gastrin receptors, we demonstrated that a number of CCK subtype selective agonists and antagonists possessed similar affinities for the vagal CCK-A and -B/gastrin receptors as those found on the guinea pig pancreas (CCK-A) and cerebral cortex (CCK-B), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Highly Potent and Subtype Selective Ligands Derived byN-Methyl Scan of a Somatostatin Antagonist

2001 ◽  
Vol 44 (8) ◽  
pp. 1305-1311 ◽  
Author(s):  
W. G. Rajeswaran ◽  
Simon J. Hocart ◽  
William A. Murphy ◽  
John E. Taylor ◽  
David H. Coy
Keyword(s):  
Selective Ligands ◽  
Somatostatin Antagonist ◽  
Subtype Selective

Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

2018 ◽  
Vol 70 (7) ◽  
pp. 910-918 ◽  
Author(s):  
Zunyuan Wang ◽  
Yewei Yang ◽  
Xiaoliang Zheng ◽  
Tao Zhang ◽  
Wenhai Huang ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Biological Evaluation ◽  
Selective Ligands ◽  
Subtype Selective ◽  
Synthesis And Biological Evaluation

Serotonergic modulation of neuronal activity in rat midbrain periaqueductal gray

2013 ◽  
Vol 109 (11) ◽  
pp. 2712-2719 ◽  
Author(s):  
Hyo-Jin Jeong ◽  
Karen Lam ◽  
Vanessa A. Mitchell ◽  
Christopher W. Vaughan
Keyword(s):  
Brain Slices ◽  
Periaqueductal Gray ◽  
Membrane Excitability ◽  
Inhibitory Effects ◽  
Whole Cell Patch Clamp ◽  
Outward Currents ◽  
Selective Ligands ◽  
Inward Currents ◽  
Subtype Selective ◽  
Serotonergic Modulation

Serotonin (5-HT) modulates pain and anxiety from within the midbrain periaqueductal gray (PAG). In the present study, the effects of 5-HT- and 5-HT1/2 subtype-selective ligands on rat PAG neurons were examined using whole cell patch-clamp recordings in brain slices. In voltage clamp, 5-HT produced outward and inward currents in distinct subpopulations of neurons that varied throughout different subregions of the PAG. The 5-HT1A agonist R(+)-8-OH-DPAT (1 μM) produced outward currents in subpopulations of PAG neurons. By contrast, sumatriptan (1 μM) and other 5-HT1B, -D, and -F subtype agonists had little or no postsynaptic activity. The 5-HT2A/C agonists DOI (3 μM) and TCB-2 (1 μM) produced inward currents in subpopulations of PAG neurons, and DOI enhanced evoked inhibitory postsynaptic currents via a presynaptic mechanism. In current clamp, both R(+)-8-OH-DPAT and sumatriptan produced an excitatory increase in evoked mixed postsynaptic potentials (PSPs). In addition, R(+)-8-OH-DPAT, but not sumatriptan, directly hyperpolarized PAG neurons. By contrast, the 5-HT2 agonist DOI depolarized subpopulations of neurons and produced an inhibitory decrease in evoked mixed PSPs. These findings indicate that 5-HT1A and 5-HT1B/D ligands have partly overlapping inhibitory effects on membrane excitability and synaptic transmission within the PAG, which are functionally opposed by 5-HT2A/C actions in specific PAG subregions.

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