scholarly journals Evaluation of Substituted N-Phenylpiperazine Analogs as D3 vs. D2 Dopamine Receptor Subtype Selective Ligands

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3182
Author(s):  
Boeun Lee ◽  
Michelle Taylor ◽  
Suzy A. Griffin ◽  
Tamara McInnis ◽  
Nathalie Sumien ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Involuntary Movement ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Inhibition Assay ◽  
D2 Dopamine Receptor ◽  
Selective Ligand ◽  
6 Hydroxydopamine ◽  
Subtype Selective

N-phenylpiperazine analogs can bind selectively to the D3 versus the D2 dopamine receptor subtype despite the fact that these two D2-like dopamine receptor subtypes exhibit substantial amino acid sequence homology. The binding for a number of these receptor subtype selective compounds was found to be consistent with their ability to bind at the D3 dopamine receptor subtype in a bitopic manner. In this study, a series of the 3-thiophenephenyl and 4-thiazolylphenyl fluoride substituted N-phenylpiperazine analogs were evaluated. Compound 6a was found to bind at the human D3 receptor with nanomolar affinity with substantial D3 vs. D2 binding selectivity (approximately 500-fold). Compound 6a was also tested for activity in two in-vivo assays: (1) a hallucinogenic-dependent head twitch response inhibition assay using DBA/2J mice and (2) an L-dopa-dependent abnormal involuntary movement (AIM) inhibition assay using unilateral 6-hydroxydopamine lesioned (hemiparkinsonian) rats. Compound 6a was found to be active in both assays. This compound could lead to a better understanding of how a bitopic D3 dopamine receptor selective ligand might lead to the development of pharmacotherapeutics for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease.

scholarly journals Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

2012 ◽  
Vol 3 (12) ◽  
pp. 1050-1062 ◽  
Author(s):  
Robert R. Luedtke ◽  
Yogesh Mishra ◽  
Qi Wang ◽  
Suzy A. Griffin ◽  
Cathy Bell-Horner ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Functional Properties ◽  
Receptor Subtype ◽  
D2 Dopamine Receptor ◽  
Subtype Selective

Differentiating the role of γ-aminobutyric acid type A (GABAA) receptor subtypes

2004 ◽  
Vol 32 (3) ◽  
pp. 553-556 ◽  
Author(s):  
K.A. Wafford ◽  
A.J. Macaulay ◽  
R. Fradley ◽  
G.F. O'Meara ◽  
D.S. Reynolds ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Acid Type ◽  
Gabaa Receptor Subtypes ◽  
Subtype Selective

The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (γ-aminobutyric acid type A) receptors. This receptor family comprises various subtypes that have unique regional distributions, but little is known about the role played by each subtype. The majority of the receptors contain a γ2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to α and β subunits. Mutagenesis studies combined with molecular modelling have enabled a greater understanding of receptor structure and dynamics. This can now be extended to in vivo activity through translation to genetically modified mice containing these mutations. Ideally, the mutation should leave normal receptor function intact, and this is the case with mutations affecting the BZ-binding site of the GABAA receptor. We have generated mutations, which affect the BZ site of different α subunits, to enable discrimination of the various behavioural consequences of BZ drug action. This has aided our understanding of the roles played by individual GABAA receptor subtypes in particular behaviours. We have also used this technique to explore the role of different β subunits in conferring the anaesthetic activity of etomidate. This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype.

scholarly journals Galanin-receptor ligand M40 peptide distinguishes between putative galanin-receptor subtypes

1993 ◽  
Vol 90 (23) ◽  
pp. 11287-11291 ◽  
Author(s):  
T Bartfai ◽  
U Langel ◽  
K Bedecs ◽  
S Andell ◽  
T Land ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Binding Sites ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Galanin Receptor ◽  
Flexor Reflex ◽  
Receptor Ligand ◽  
Insulinoma Cells ◽  
Galanin Receptors

The galanin-receptor ligand M40 [galanin-(1-12)-Pro3-(Ala-Leu)2-Ala amide] binds with high affinity to [mono[125I]iodo-Tyr26]galanin-binding sites in hippocampal, hypothalamic, and spinal cord membranes and in membranes from Rin m5F rat insulinoma cells (IC50 = 3-15 nM). Receptor autoradiographic studies show that M40 (1 microM) displaces [mono[125I]iodo-Tyr26]galanin from binding sites in the hippocampus, hypothalamus, and spinal cord. In the brain, M40 acts as a potent galanin-receptor antagonist: M40, in doses comparable to that of galanin, antagonizes the stimulatory effects of galanin on feeding, and it blocks the galaninergic inhibition of the scopolamine-induced acetylcholine release in the ventral hippocampus in vivo. In contrast, M40 completely fails to antagonize both the galanin-mediated inhibition of the glucose-induced insulin release in isolated mouse pancreatic islets and the inhibitory effects of galanin on the forskolin-stimulated accumulation of 3',5'-cAMP in Rin m5F cells; instead M40 is a weak agonist at the galanin receptors in these two systems. M40 acts as a weak antagonist of galanin in the spinal flexor reflex model. These results suggest that at least two subtypes of the galanin receptor may exist. Hypothalamic and hippocampal galanin receptors represent a putative central galanin-receptor subtype (GL-1-receptor) that is blocked by M40. The pancreatic galanin receptor may represent another subtype (GL-2-receptor) that recognizes M40, but as a weak agonist. The galanin receptors in the spinal cord occupy an intermediate position between these two putative subtypes.

scholarly journals In Vivo Activity of the Thyroid Hormone Receptor β- and α-Selective Agonists GC-24 and CO23 on Rat Liver, Heart, and Brain

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1136-1142 ◽  
Author(s):  
Carmen Grijota-Martínez ◽  
Eric Samarut ◽  
Thomas S. Scanlan ◽  
Beatriz Morte ◽  
Juan Bernal
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Genetic Modifications ◽  
Hormone Analogs ◽  
Thyroid Hormone Receptor Β

Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TRβ-selective GC-24 and the TRα-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TRβ and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TRα or TRβ. This compound, previously shown to be TRα-selective in tadpoles, displayed no selectivity in the rat in vivo.

scholarly journals Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Haruo Nishijima ◽  
Yasuo Miki ◽  
Shinya Ueno ◽  
Masahiko Tomiyama
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Involuntary Movement ◽  
Dopamine Metabolism ◽  
Dopamine Receptor Agonist ◽  
D2 Dopamine Receptor ◽  
Once Daily ◽  
6 Hydroxydopamine ◽  
Motor Effects

Zonisamide is a relatively recent drug for Parkinson’s disease. Multiple hypotheses have been proposed to explain the antiparkinsonian effects of zonisamide. However, it is still unclear whether the effect of zonisamide is mainly due to dopaminergic modification in the striatum, or if zonisamide works through nondopaminergic pathways. We conducted the present study to determine the mechanism that is mainly responsible for zonisamide’s effects in Parkinson’s disease. We examined the effects of zonisamide on motor symptoms in a hemiparkinsonian rat model when administered singly, coadministered with levodopa, a dopamine precursor, or apomorphine, a D1 and D2 dopamine receptor agonist. We used 6-hydroxydopamine-lesioned hemiparkinsonian rats, which were allocated to one of five groups: 14 rats received levodopa only (6 mg/kg), 12 rats received levodopa (6 mg/kg) plus zonisamide (50 mg/kg), six rats received apomorphine only (0.05 mg/kg), six rats received apomorphine (0.05 mg/kg) plus zonisamide (50 mg/kg), and six rats received zonisamide only (50 mg/kg). The drugs were administered once daily for 15 days. We evaluated abnormal involuntary movement every 20 min during a 3 h period following the injection of drugs on treatment Days 1, 8, and 15. Western blot analyses for dopamine decarboxylase and vesicular monoamine transferase-2 were performed using striatal tissues in the lesioned side of rats in the levodopa only group (n = 6) and levodopa plus zonisamide group (n = 4). Levodopa-induced abnormal involuntary movement was significantly enhanced by coadministration of zonisamide. In contrast, zonisamide had no effect on apomorphine-induced abnormal involuntary movement. Zonisamide monotherapy did not induce abnormal involuntary movement. Zonisamide did not affect striatal expression of dopamine decarboxylase or vesicular monoamine transferase-2. In conclusion, zonisamide appears to generate its antiparkinsonian effects by modulating levodopa-dopamine metabolism in the parkinsonian striatum.

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