P.3.072 Bifeprunox: a novel partial agonist for the D2 receptor with antagonistic capabilities depending on dopaminergic tone

2005 ◽  
Vol 15 ◽  
pp. S486 ◽  
Keyword(s):  
Partial Agonist ◽  
D2 Receptor ◽  
Dopaminergic Tone

scholarly journals Dopamine receptors mediate strategy abandoning via modulation of a specific prelimbic cortex–nucleus accumbens pathway in mice

2018 ◽  
Vol 115 (21) ◽  
pp. E4890-E4899 ◽  
Author(s):  
Qiaoling Cui ◽  
Qian Li ◽  
Hongyan Geng ◽  
Lei Chen ◽  
Nancy Y. Ip ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Receptors ◽  
Cortical Neurons ◽  
Critical Role ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Prelimbic Cortex ◽  
Dopamine Depletion ◽  
Dopaminergic Tone ◽  
Type Receptor

The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex–nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex–NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.

“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

2021 ◽  
Vol 3 (1) ◽  
pp. 033-040
Author(s):  
Keiko Ikemoto
Keyword(s):  
Medicinal Chemistry ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Immunohistochemical Method ◽  
Post Mortem ◽  
Background Theory ◽  
Related Substances ◽  
Post Mortem Brain ◽  
Receptor Profile ◽  
D Cell

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.

scholarly journals Modeling of ligand binding to dopamine D2 receptor

2014 ◽  
Vol 79 (2) ◽  
pp. 175-183 ◽  
Author(s):  
Liliana Ostopovici-Halip ◽  
Ramona Rad-Curpan
Keyword(s):  
Dopamine D2 Receptor ◽  
Partial Agonist ◽  
3D Structure ◽  
D2 Receptor ◽  
Salt Bridge ◽  
Binding Mode ◽  
Receptor Binding Site ◽  
Hydrogen Bond Formation ◽  
Essential Information ◽  
Partial Agonists

The dopaminic receptors have been for long time the major targets for developing new small molecules with high affinity and selectivity to treat psychiatric disorders, neurodegeneration, drug abuse, and other therapeutic areas. In the absence of a 3D structure for the human D2 dopamine (HDD2) receptor, the efforts for discovery and design of new potential drugs rely on comparative models generation, docking and pharmacophore development studies. To get a better understanding of the HDD2 receptor binding site and the ligand-receptor interactions a homology model of HDD2 receptor based on the X-ray structure of ?2-adrenergic receptor has been built and used to dock a set of partial agonists of HDD2 receptor. The main characteristics of the binding mode for the HDD2 partial agonists set are given by the ligand particular folding and a complex network of contacts represented by stacking interactions, salt bridge and hydrogen bond formation. The characterization of the partial agonist binding mode at HDD2 receptor provide the needed information to generate pharmacophore models which represent essential information in the future virtual screening studies in order to identify new potential HDD2 partial agonists.

scholarly journals Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors

2012 ◽  
Vol 16 (2) ◽  
pp. 445-458 ◽  
Author(s):  
Jack Bergman ◽  
Rebecca A. Roof ◽  
Cheryse A. Furman ◽  
Jennie L. Conroy ◽  
Nancy K. Mello ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Abuse Liability ◽  
Cocaine Addiction ◽  
Dose Effect ◽  
Self Administration ◽  
Binding Studies ◽  
High Affinity ◽  
Reinforcing Effects

Abstract Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (∼98 and ∼29 nm respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose–effect function for cocaine-maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction.

scholarly journals Effects of 2-bromoterguride, a dopamine D2 receptor partial agonist, on cognitive dysfunction and social aversion in rats

2017 ◽  
Vol 235 (1) ◽  
pp. 99-108 ◽  
Author(s):  
Emilia Tarland ◽  
Robert T. Franke ◽  
Heidrun Fink ◽  
Heinz H. Pertz ◽  
Jan Brosda
Keyword(s):  
Cognitive Dysfunction ◽  
Dopamine D2 Receptor ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Dopamine D2

Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist

2006 ◽  
Vol 552 (1-3) ◽  
pp. 36-45 ◽  
Author(s):  
Julia N. Heinrich ◽  
Julie Brennan ◽  
Margaret H. Lai ◽  
Kelly Sullivan ◽  
Geoff Hornby ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
Partial Agonist ◽  
D2 Receptor ◽  
High Affinity ◽  
Dopamine D2 ◽  
Selective Dopamine

scholarly journals Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function

2021 ◽  
Author(s):  
Anni Richter ◽  
Lieke de Boer ◽  
Marc Guitart-Masip ◽  
Gusalija Behnisch ◽  
Constanze I. Seidenbecher ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Receptor Expression ◽  
Learning Performance ◽  
Genetic Determinants ◽  
Learning Differences ◽  
Total N ◽  
Learning Biases ◽  
Motivated Behavior ◽  
Dopaminergic Tone

Dopaminergic neurotransmission plays a pivotal role in appetitively motivated behavior in mammals, including humans. Notably, action and valence are not independent in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward. We have previously observed that the carriers of the DRD2/ANKK1 TaqIA A1 allele, that has been associated with reduced striatal dopamine D2 receptor expression, showed a diminished learning performance when required to learn response inhibition to obtain rewards, a finding that was replicated in two independent cohorts. In the present study, we first report a replication of this finding in a third independent cohort of 99 participants. Interestingly, after combining all three cohorts (total N = 281), exploratory analyses regarding the COMT Val108/158Met polymorphism suggest that homozygotes for the Met allele, which has been linked to higher prefrontal dopaminergic tone, show a lower learning bias. Our results corroborate the importance of genetic variability of the dopaminergic system in individual learning differences of action-valence interaction and, furthermore, suggest that motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function.

The Dopamine D2 Receptor Partial Agonist Antipsychotics, Aripiprazole, and Brexpiprazole

2021 ◽  
pp. 1-45
Author(s):  
Tetsuro Kikuchi ◽  
Kenji Maeda ◽  
Sakiko Yamada ◽  
Mikio Suzuki ◽  
Tsuyoshi Hirose ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Dopamine D2
Sign in / Sign up

Export Citation Format

Share Document