scholarly journals trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT2 receptor family

2012 ◽  
Vol 8 ◽  
pp. 1705-1709 ◽  
Author(s):  
Adam Pigott ◽  
Stewart Frescas ◽  
John D McCorvy ◽  
Xi-Ping Huang ◽  
Bryan L Roth ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Side Chain ◽  
Receptor Subtypes ◽  
Receptor Function ◽  
High Affinity ◽  
Receptor Family

A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT2 family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (−)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT2A and 5-HT2B receptors. Therefore, at appropriate doses – although (−)-4 and (−)-5 may be useful as tools to probe 5-HT2 receptor function – one would need to be mindful that their selectivity for 5-HT2A receptors is somewhat less than for DOI itself.

Cholecystokinin receptors

1995 ◽  
Vol 269 (5) ◽  
pp. G628-G646 ◽  
Author(s):  
S. A. Wank
Keyword(s):  
Function Analysis ◽  
Receptor Gene ◽  
Wide Distribution ◽  
Receptor Expression ◽  
Receptor Subtypes ◽  
Cck Receptors ◽  
High Affinity ◽  
Recombinant Receptor ◽  
Receptor Pharmacology ◽  
Specific Variation

The cholecystokinin (CCK) and gastrin families of peptides act as hormones and neuropeptides on central and peripheral CCK receptors to mediate secretion and motility in the gastrointestinal (GI) tract in the physiological response to a normal meal. CCK and its receptors are also widely distributed in the central nervous system (CNS) and contribute to the regulation of satiety, anxiety, analgesia, and dopamine-mediated behavior. Although the wide distribution, myriad number of functions, and reported pharmacological heterogeneity of CCK receptors would suggest a large number of receptor subtypes, the application of modern molecular biological techniques has identified two CCK receptors, CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR), that mediate the actions of CCK and gastrin; gastrin receptors have been found to be identical to CCK-BR. CCK-AR, found predominantly in the GI system and select areas of the CNS, have high affinity for CCK and the nonpeptide antagonist L-364,718, whereas CCK-BR, found predominantly in the CNS and select areas of the GI system, have high affinity for CCK and gastrin and the nonpeptide antagonist L-365,260. Both CCK-AR and CCK-BR are highly conserved between species, although there is some tissue-specific variation in expression. Recombinant receptor expression faithfully reproduces the native receptor pharmacology and signal transduction pathways, allowing direct comparisons of receptor function between species as well as serving as a convenient source of receptor. Our present knowledge of the chromosomal localization, receptor gene structure, and primary sequence will allow further studies in disease association, receptor regulation, and structure-function analysis.

scholarly journals Gating Competence of Constitutively Open CLC-0 Mutants Revealed by the Interaction with a Small Organic Inhibitor

2003 ◽  
Vol 122 (3) ◽  
pp. 295-306 ◽  
Author(s):  
Sonia Traverso ◽  
Laura Elia ◽  
Michael Pusch
Keyword(s):  
Chloride Channels ◽  
Bound State ◽  
Side Chain ◽  
Pore Channel ◽  
Kinetic Properties ◽  
Wild Type ◽  
High Affinity ◽  
Critical Residue ◽  
Fast Gating

Opening of CLC chloride channels is coupled to the translocation of the permeant anion. From the recent structure determination of bacterial CLC proteins in the closed and open configuration, a glutamate residue was hypothesized to form part of the Cl−-sensitive gate. The negatively charged side-chain of the glutamate was suggested to occlude the permeation pathway in the closed state, while opening of a single protopore of the double-pore channel would reflect mainly a movement of this side-chain toward the extracellular pore vestibule, with little rearrangement of the rest of the channel. Here we show that mutating this critical residue (Glu166) in the prototype Torpedo CLC-0 to alanine, serine, or lysine leads to constitutively open channels, whereas a mutation to aspartate strongly slowed down opening. Furthermore, we investigated the interaction of the small organic channel blocker p-chlorophenoxy-acetic acid (CPA) with the mutants E166A and E166S. Both mutants were strongly inhibited by CPA at negative voltages with a >200-fold larger affinity than for wild-type CLC-0 (apparent KD at −140 mV ∼4 μM). A three-state linear model with an open state, a low-affinity and a high-affinity CPA-bound state can quantitatively describe steady-state and kinetic properties of the CPA block. The parameters of the model and additional mutagenesis suggest that the high-affinity CPA-bound state is similar to the closed configuration of the protopore gate of wild-type CLC-0. In the E166A mutant the glutamate side chain that occludes the permeation pathway is absent. Thus, if gating consists only in movement of this side-chain the mutant E166A should not be able to assume a closed conformation. It may thus be that fast gating in CLC-0 is more complex than anticipated from the bacterial structures.

scholarly journals 68Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5

2004 ◽  
Vol 32 (6) ◽  
pp. 724-724 ◽  
Author(s):  
Damian Wild ◽  
Helmut R. Mäcke ◽  
Beatrice Waser ◽  
Jean Claude Reubi ◽  
Mihaela Ginj ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Somatostatin Receptor ◽  
Receptor Subtypes ◽  
High Affinity ◽  
Somatostatin Receptor Subtypes

Serotonin Receptor Subtypes: Implications for Psychopharmacology

1991 ◽  
Vol 159 (S12) ◽  
pp. 7-14 ◽  
Author(s):  
P. J. Cowen
Keyword(s):  
Cognitive Processes ◽  
Serotonin Receptor ◽  
Antidepressant Treatment ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Controlled Clinical Trials ◽  
Wide Range ◽  
Selective Ligands ◽  
Coupling Mechanisms ◽  
Therapeutic Possibilities

Serotonin (5-HT) interacts with multiple brain 5-HT receptor subtypes to influence a wide range of behaviours. Three main families of 5-HT receptors (5-HT1, 5-HT2 and 5-HT3) have been described which differ in their binding affinity for selective ligands, their receptor-effector coupling mechanisms, and the behavioural processes they regulate. Nevertheless, manipulation of several different 5-HT receptor subtypes (5-HT1A, 5-HT1c, 5-HT2 and 5-HT3) may produce anxiolytic effects; 5-HT1A and 5-HT2 receptors may be involved in the aetiology of major depression and the therapeutic effects of antidepressant treatment; and 5-HT3 receptors have been linked to reward mechanisms and cognitive processes. These advances offer therapeutic possibilities, the value of which can only be satisfactorily assessed by controlled clinical trials.

Serotonin Receptor Subtypes

1993 ◽  
pp. 15-25 ◽  
Author(s):  
P. R. Hartig ◽  
N. Adham ◽  
J. Zgombick ◽  
M. Macchi ◽  
H.-T. Kao ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Receptor Subtypes

scholarly journals Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nataliya Gorinski ◽  
Monika Bijata ◽  
Sonal Prasad ◽  
Alexander Wirth ◽  
Dalia Abdel Galil ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Receptor Function
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