LB50053: a 5-hydroxytrypamine(1a) agent with a high binding affinity and a potency evoking a K(+) current.
The newly synthesized N-substituted derivative of 3-aryl-pyrrolidine LB50053, 2-[4-[3-(4-fluoro)-phenylpyrrolidine-1-yl] - butyl]-1,2- benzisothiazol -3(2H)-one-1,1-dioxide, was studied in receptor-binding assays and in electrophysiological measurements. Competitive binding experiments with various radioligands to the rat fore-brain revealed that the (S)-enantiomer of LB50053 had a high affinity (Ki 4.2 nmol/l) and a high selectivity for 5-HT(1A) receptors as compared with 5-HT(2A), D(1) dopamine, D(2) dopamine, or (alpha(2)-adrenergic receptor. In Xenopus oocytes, where coupling of the 5-HT(1A) receptor to the G protein activated inwardly rectifying K(+) channel 1(GIRK1) was established, (S)-LB50053 evoked an inward K(+) current through GIRK1 in a manner consistent with a partial agonism. The K(d) value deduced from the dose-response relationships of the 5-HT(1A) receptor full agonist 8-OH-2-(di-n-propylamino)-1,2,3,4-tetrahydronaphthalene and (S)-LB50053 according to Waud analysis was 64.60 nmol/l. These results demonstrate that LB50053 is a 5-HT(1A) receptor partial agonist and thus can be used asa therapeutic or pharmacological research tool for 5-HT(1A) receptor mediated events in the future.
Kim
Han-Seop
HS
Department of Biological Sciences, Ajou University, Suwon, South Korea.
Cho
Taesup
T
Lee
Changho
C
Joo
Hyun
H
Kim
Seung
S
Min
Churl K
CK
D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D066298:In Vitro Techniques; D009865:Oocytes; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D011760:Pyrrolidinones / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013844:Thiazoles / Q000494:pharmacology*; D014982:Xenopus laevis
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C470907:LB 50053; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011760:Pyrrolidinones; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D013844:Thiazoles