title: Pharmacologic characterization of CHIR 2279, an N-substituted glycine peptoid with high-affinity binding for alpha 1-adrenoceptors.
abstract: We characterize the in vitro and in vivo pharmacology of CHIR 2279, an N-substituted glycine peptoid previously identified from a combinatorial library as a novel ligand to alpha 1-adrenoceptors. Competitive receptor-binding assays with [3H]prazosin showed that CHIR 2279 was similar to prazosin in binding to alpha 1A (rat submaxillary), alpha 1a, alpha 1b, and alpha 1 d (cDNA expressed in LTK- cells) with high and approximately equipotent affinity. Ki values for CHIR 2279 ranged from 0.7 to 3 nM, and were 10-fold weaker than with prazosin. Functional assays for postsynaptic alpha 1-adrenoceptors showed CHIR 2279 was approximately equipotent in antagonizing agonist-induced contractile responses with rat was deferens (alpha 1A), canine prostate (alpha 1A), rat spleen (alpha 1B) and rat aorta (alpha 1D). The pA2 for CHIR 2279 averaged 7.07 in these assays, indicating a 10- to 100-fold lower in vitro potency than prazosin. In dogs, CHIR 2279 antagonized the epinephrine-induced increase in intraurethal pressure (pseudo pA2, 6.86) and in rats antagonized the phenylephrine-induced increase in mean arterial blood pressure. In rats and guinea pigs, CHIR 2279 induced a dose-dependent decrease in mean arterial blood pressure without eliciting the tachycardia commonly observed with other alpha 1-blockers. Pharmacokinetic/pharmacodynamic modeling showed the i.v. system clearance rate of CHIR 2279 was 60 and 104 ml/min/kg in rats and guinea pigs, respectively, and the in vivo potency for mean arterial blood pressure reduction was twice as great in guinea pigs (EC50, 520 ng/ml) than rats (EC50, 1170 ng/ml).
authors.affiliation: Chiron Corporation, Emeryville, California, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gibbons
authors.forename: A A
authors.initials: AA
authors.lastname: Hancock
authors.forename: C R
authors.initials: CR
authors.lastname: Vitt
authors.forename: S
authors.initials: S
authors.lastname: Knepper
authors.forename: S A
authors.initials: SA
authors.lastname: Buckner
authors.forename: M E
authors.initials: ME
authors.lastname: Brune
authors.forename: I
authors.initials: I
authors.lastname: Milicic
authors.forename: J F
authors.initials: JF
authors.lastname: Kerwin
authors.forename: L S
authors.initials: LS
authors.lastname: Richter
authors.forename: E W
authors.initials: EW
authors.lastname: Taylor
authors.forename: K L
authors.initials: KL
authors.lastname: Spear
authors.forename: R N
authors.initials: RN
authors.lastname: Zuckermann
authors.forename: D C
authors.initials: DC
authors.lastname: Spellmeyer
authors.forename: R A
authors.initials: RA
authors.lastname: Braeckman
authors.forename: W H
authors.initials: WH
authors.lastname: Moos
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D034444:Peptoids; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013045:Species Specificity; D014521:Urethra / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D009842:Oligopeptides; D034444:Peptoids; D018340:Receptors, Adrenergic, alpha-1; C088972:CHIR 2279; D011224:Prazosin