title: Synthesis and biological activity of a GABAA agonist which has no effect on benzodiazepine binding and of structurally related glycine antagonists.
abstract: 3-Isoxazolols substituted in the 5-position by pyrrolidinyl or piperidyl (referred to, respectively, as PYOLs and PIOLs; see Figure 2 for structures) were designed and synthesized as analogues of the potent and specific GABAA agonist THIP. Activity in the series was markedly dependent upon positional isomerism in the structures. Isomers in which the pyrrolidine or piperidine rings were attached via their 2-positions (2-PYOL and 2-PIOL) had no effect on GABAA receptors in vivo or in vitro. An isomer wherein attachment was via the 4-position (4-PIOL) was a GABAA agonist, but it was unique in not affecting the binding of diazepam in vitro; its 'ring-opened' analogue, (RS)-5-(1-methyl-3-aminopropyl)-3-isoxazolol (11) did not bind significantly to GABAA receptor sites in vitro. In contrast, the 3-positional isomer (3-PIOL) antagonized the inhibitory action of glycine on cat spinal neurons. A similar effect was earlier demonstrated for 3-PYOL. However, in contrast to 3-PYOL, which is approximately equipotent as an antagonist of glycine and GABA, 3-PIOL only marginally reduced the inhibitory effect of GABA. The R and S forms of 3-PIOL, synthesized from the respective isomers of piperidine-3-carboxylic acid with known absolute stereochemistry, had pharmacological profiles indistinguishable from that of racemic 3-PIOL.
authors.affiliation: Department of Chemistry BC, Royal Danish School of Pharmacy, Copenhagen, Denmark.
authors.forename: J R
authors.initials: JR
authors.lastname: Byberg
authors.forename: I M
authors.initials: IM
authors.lastname: Labouta
authors.forename: E
authors.initials: E
authors.lastname: Falch
authors.forename: H
authors.initials: H
authors.lastname: Hjeds
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: D R
authors.initials: DR
authors.lastname: Curtis
authors.forename: B D
authors.initials: BD
authors.lastname: Gynther
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D005998:Glycine / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis*; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D007555:Isoxazoles; D010080:Oxazoles; D010880:Piperidines; D011759:Pyrrolidines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; D005998:Glycine; D001640:Bicuculline