Effects of the selective 5-HT1A receptor antagonist WAY100135 and its enantiomers on 8-OH-DPAT-induced hyperglycaemia in conscious rats.
8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increases plasma glucose levels in conscious rats probably by stimulation of central 5-HT1A receptors. We have examined the effects of WAY100135 (N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropan amide), a selective 5-HT1A receptor antagonist and its enantiomers on plasma glucose levels and on the hyperglycaemia induced by 8-OH-DPAT. (R,S)-WAY100135 (minimum effective dose (MED) 3 mg/kg i.v.) and (S)-WAY100135 (MED 1 mg/kg i.v.) dose-dependently attenuated 8-OH-DPAT-induced hyperglycaemia. In contrast, (R)-WAY100135 at doses up to 3 mg/kg i.v. was unable to block hyperglycaemia induced by 8-OH-DPAT. When the antagonists were examined for intrinsic effects on plasma glucose levels only (S)-WAY100135 (3 mg/kg i.v.) caused a significant but transient hyperglycaemia (20% increase). These results are consistent with previous suggestions that (R,S)-WAY100135 and (S)-WAY100135 are selective 5-HT1A receptor antagonists and that 8-OH-DPAT-induced hyperglycaemia is mediated by 5-HT1A receptors. The antagonist action of WAY100135 is stereoselective, and more potent activity being observed with the (S) enantiomer.
Critchley
D J
DJ
Department of Neuropharmacology, Wyeth Research (UK) Ltd., Maidenhead, Berkshire, UK.
Middlefell
V C
VC
Liddle
C W
CW
Foden
N D
ND
Dourish
C T
CT
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006943:Hyperglycemia / Q000139:chemically induced*; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism
D001786:Blood Glucose; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081293:WAY 100135; C056895:flesinoxan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011224:Prazosin