Evaluation of the α2C-adrenoceptor as a neuropsychiatric drug target

Scheinin, Mika; Sallinen, Jukka; Haapalinna, Antti

doi:10.1016/s0024-3205(01)01016-5

Cited by 89 publications

(77 citation statements)

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“…PET tracers are needed for imaging of this receptor system in vivo. Methods: High-specific-activity 11 C-ORM-13070 (1-[(S)-1-(2,3-dihydrobenzo [1,4]dioxin-2-yl)methyl]-4-(3-11 C-methoxymethylpyridin-2-yl)-piperazine) was synthesized by 11 C-methylation of O-desmethyl-ORM-13070 with 11 C-methyl triflate, which was prepared from cyclotron-produced 11 C-methane via 11 C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography.…”

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confidence: 99%

“…The a 2C adrenoceptor subtype is a potential drug target for the treatment of neuropsychiatric disorders, such as depression, schizophrenia, and dementia (1,2).…”

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confidence: 99%

“…We report here the radiosynthesis of 11 C-ORM-13070 (1-[(S)-1-(2,3-dihydrobenzo [1,4]dioxin-2-yl)methyl]-4-(3-11 C-methoxymethylpyridin-2-yl)-piperazine) with high specific activity (SA). The receptor specificity of 11 C-ORM-13070 binding was assessed ex vivo in rats using pretreatment with atipamezole (Antisedan; Orion Pharma), a subtype-nonselective antagonist of a 2 adrenoceptors.…”

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A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

et al. 2014

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We report the development of a PET tracer for α 2C adrenoceptor imaging and its preliminary preclinical evaluation. α 2C adrenoceptors in the human brain may be involved in various neuropsychiatric disorders, such as depression, schizophrenia, and neurodegenerative diseases. PET tracers are needed for imaging of this receptor system in vivo. Methods: High-specific-activity 11 C-ORM-13070 (1--(3-11 C-methoxymethylpyridin-2-yl)-piperazine) was synthesized by 11 C-methylation of O-desmethyl-ORM-13070 with 11 C-methyl triflate, which was prepared from cyclotron-produced 11 C-methane via 11 C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography. The specificity of 11 C-ORM-13070 binding to α 2 adrenoceptors was demonstrated in rats pretreated with atipamezole, an α 2 adrenoceptor antagonist. The α 2C adrenoceptor selectivity of the tracer was determined by comparing tracer binding in wild-type and α 2A -and α 2AC adrenoceptor knockout (KO) mice. 11 C-ORM-13070 and its radioactive metabolites in rat plasma and brain tissue were analyzed with radio-high-performance liquid chromatography and mass spectroscopy. Human radiation dose estimates were extrapolated from rat biodistribution data. Results: The radiochemical yield, calculated from initial cyclotron-produced 11 C-methane, was 9.6% ± 2.7% (decaycorrected to end of bombardment). The specific activity of the product was 640 ± 390 GBq/μmol (decay-corrected to end of synthesis). The radiochemical purity exceeded 99% in all syntheses. The highest levels of tracer binding were observed in the striatum and olfactory tubercle of rats and control and α 2A KO mice-that is, in the brain regions known to contain the highest densities of α 2C adrenoceptors. In rats pretreated with atipamezole and in α 2AC KO mice, 11 C tracer binding in the striatum and olfactory tubercle was low, similar to that of the frontal cortex and thalamus, regions with low densities of α 2C adrenoceptors. Two radioactive metabolites were found in rat plasma, but only one of them was found in the brain; their identity was not revealed. The estimated effective radiation dose was comparable with the average exposure level in PET studies with 11 C tracers. Conclusion: An efficient method for the radiosynthesis of 11 C-ORM-13070 was developed. 11 C-ORM-13070 emerged as a potential novel radiotracer for in vivo imaging of brain α 2C adrenoceptors.

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confidence: 99%

“…The a 2C adrenoceptor subtype is a potential drug target for the treatment of neuropsychiatric disorders, such as depression, schizophrenia, and dementia (1,2).…”

mentioning

confidence: 99%

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confidence: 99%

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A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

et al. 2014

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“…Homologous recombination strategies that lead either to gene knockouts or a substitution of a mutant receptor at the wild-type locus in the mouse genome have been developed. Using genetically engineered mouse strains it has been suggested that the ␣ 2C -AR subtype has a distinct inhibitory role in the processing of sensory information and in the control of motor and emotion-related activities in the central nervous system (Scheinin et al, 2001). It is therefore possible that ␣ 2C -AR-selective drugs may have therapeutic value in the treatment of various neuropsychiatric disorders.…”

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confidence: 99%

Yohimbine Dimers Exhibiting Selectivity for the Human α_2c-Adrenoceptor Subtype

Lalchandani

Lei

Zheng

et al. 2002

J Pharmacol Exp Ther

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Yohimbine is a potent and selective ␣ 2 -versus ␣ 1 -adrenoceptor antagonist. To date, drugs with high specificity for the ␣ 2 -adrenoceptor show marginal selectivity among the three ␣ 2 -adrenoceptor subtypes. Initial studies showed that yohimbine was about 4-and 15-fold more selective for the human ␣ 2C -adrenoceptor in comparison with the ␣ 2A -and ␣ 2B -adrenoceptors, respectively. To improve on this ␣ 2 -adrenoceptor subtype selectivity, a series of yohimbine dimers (varying from n ϭ 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human ␣ 2 -adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for ␣ 2A -and ␣ 2C -adrenoceptor versus the ␣ 2B -adrenoceptor; and yohimbine dimers with spacers of n ϭ 2, 3, 4, 18, and 24 exhibited selectivity for the ␣ 2C -adrenoceptor. The yohimbine dimers n ϭ 3 and n ϭ 24 showed the highest potency and selectivity (32-and 82-fold. respectively) for the ␣ 2C -adrenoceptor in receptor binding and in functional studies (42-and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay. The dimers (n ϭ 3 and n ϭ 24) had high selectivity (Ͼ1000-fold) for the ␣ 2C -adrenoceptor compared with the three ␣ 1 -adrenoceptor subtypes. These findings demonstrate that the addition of spacer linkages to bivalent yohimbine molecules provides a successful approach to the development of ligands that are potent and highly selective for the ␣ 2C -adrenoceptor.

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“…Peterhoff et al (2003) used knockout mice to report that the ␣ 2A -and ␣ 2C -ARs mediate epinephrine-induced inhibition of insulin secretion in pancreatic islet cells. In the central nervous system, the ␣ 2C -ARs seem to have a distinct inhibitory role in various central nervous system-mediated behavioral and physiological responses including startle reactivity, aggressive behavior, and amphetamine-induced locomotor hyperactivity (Scheinin et al, 2001). Thus, increased ␣ 2C -AR activity may lead to or result from a constitutively stressful state, thereby causing depression, which suggests that ␣ 2C -AR subtype-selective drugs may be useful in a variety of neuropsychiatric disorders (Scheinin et al, 2001).…”

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Tethered Yohimbine Analogs as Selective Human α_2C-Adrenergic Receptor Ligands

Bavadekar¹,

Ma²,

Mustafa³

et al. 2006

J Pharmacol Exp Ther

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Yohimbine is a potent and relatively nonselective ␣ 2 -adrenergic receptor (AR) antagonist. In an earlier report, we demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human ␣ 2C -AR ligands. Little work has been done to examine the role of the tether group or the absence of the second yohimbine pharmacophore on selectivity for human ␣ 2 -AR subtypes. The goal of our study was to determine the binding affinities and functional subtype selectivities of a series of tethered yohimbine ligands in the absence of the second pharmacophore. The profiles of pharmacological activity for the yohimbine analogs on the three human ␣ 2 -AR subtypes expressed in Chinese hamster ovary cells were examined using receptor binding and cAMP inhibition assays. All of the tethered yohimbine analogs exhibited higher binding affinities at the ␣ 2C -versus ␣ 2A -and ␣ 2B -AR subtypes. Notably, the benzyl carboxy alkyl amine and the carboxy alkyl amine analogs exhibited 43-and 1995-fold and 295-and 54-fold selectivities in binding to the ␣ 2C -versus ␣ 2A -and ␣ 2B -ARs, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities and selectivity profiles of selected compounds from the tethered series. The data demonstrate that the second pharmacophore may not be essential to obtain ␣ 2C -AR subtype selectivity, previously observed with the dimers. Further changes in the nature of the tether will help in optimization of the structureactivity relationship to obtain potent and selective ␣ 2C -AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.

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Evaluation of the α2C-adrenoceptor as a neuropsychiatric drug target

Cited by 89 publications

References 0 publications

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

Yohimbine Dimers Exhibiting Selectivity for the Human α_2c-Adrenoceptor Subtype

Tethered Yohimbine Analogs as Selective Human α_2C-Adrenergic Receptor Ligands

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Evaluation of the α2C-adrenoceptor as a neuropsychiatric drug target

Cited by 89 publications

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A PET Tracer for Brain α2C Adrenoceptors, 11C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

A PET Tracer for Brain α2C Adrenoceptors, 11C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

Yohimbine Dimers Exhibiting Selectivity for the Human α2c-Adrenoceptor Subtype

Tethered Yohimbine Analogs as Selective Human α2C-Adrenergic Receptor Ligands

Contact Info

Product

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A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

A PET Tracer for Brain α_2C Adrenoceptors, ¹¹C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice

Yohimbine Dimers Exhibiting Selectivity for the Human α_2c-Adrenoceptor Subtype

Tethered Yohimbine Analogs as Selective Human α_2C-Adrenergic Receptor Ligands