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FältnamnIndikatorerMetadata
00005814naa a2200661 4500
001oai:gup.ub.gu.se/297226
003SwePub
008240528s2020 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:144718802
0247 a https://gup.ub.gu.se/publication/2972262 URI
0247 a https://doi.org/10.1124/jpet.120.0000372 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1447188022 URI
040 a (SwePub)gud (SwePub)ki
041 a eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Hjorth, Stephan,d 1953u Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine4 aut0 (Swepub:gu)xhjost
2451 0a (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752)-a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent
264 c 2020-06-30
264 1b American Society for Pharmacology & Experimental Therapeutics (ASPET),c 2020
520 a Here we describe for the first time the distinctive pharmacological profile for (35)-3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mu mol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypo-activity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to similar to 250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to similar to 250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptannine 7 receptor and alpha 2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on cate-cholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmakologi och toxikologi0 (SwePub)301022 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmacology and Toxicology0 (SwePub)301022 hsv//eng
653 a medial prefrontal cortex
653 a serotonin 5-ht7 receptor
653 a object recognition
653 a task
653 a parkinsons-disease
653 a extracellular concentrations
653 a antipsychotic-drugs
653 a multimodal antidepressant
653 a atypical antipsychotics
653 a acetylcholine-release
653 a nonmotor symptoms
653 a Pharmacology & Pharmacy
7001 a Waters, S.4 aut
7001 a Waters, N.4 aut
7001 a Tedroff, J.u Karolinska Institutet4 aut
7001 a Svensson, P.4 aut
7001 a Fagerberg, A.4 aut
7001 a Edling, M.4 aut
7001 a Svanberg, B.4 aut
7001 a Ljung, E.4 aut
7001 a Gunnergren, J.4 aut
7001 a McLean, S. L.4 aut
7001 a Grayson, B.4 aut
7001 a Idris, N. F.4 aut
7001 a Neill, J. C.4 aut
7001 a Sonesson, C.4 aut
7102 a Göteborgs universitetb Institutionen för medicin, avdelningen för molekylär och klinisk medicin4 org
7730 t Journal of Pharmacology and Experimental Therapeuticsd : American Society for Pharmacology & Experimental Therapeutics (ASPET)g 374:3, s. 404-419q 374:3<404-419x 0022-3565x 1521-0103
8564 u https://jpet.aspetjournals.org/content/jpet/374/3/404.full.pdf
8564 8u https://gup.ub.gu.se/publication/297226
8564 8u https://doi.org/10.1124/jpet.120.000037
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:144718802

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