PGE-6201204

1 Pig nasal mucosal strips were incubated with α‐adrenoceptor antagonists followed by α2‐adrenoceptor agonist concentration–response curves.2 Contractions elicited by the α2‐adrenoceptor agonists BHT‐920 (pD2 = 6.16 ± 0.07), UK 14,304 (pD2 = 6.89 ± 0.13) and PGE‐6201204 (pD2 = 7.12 ± 0.21) were blocked by the α2‐adrenoceptor antagonist yohimbine (0.1 μm). In contrast, the α1‐adrenoceptor antagonist prazosin (0.03 μm) had no effect on the BHT‐920‐, UK 14,304‐ and PGE‐6201204‐induced contractions, but blocked the contractile response to the α1‐adrenoceptor agonist phenylephrine (pD2 = 5.38 ± 0.04) and the mixed α1‐ and α2‐adrenoceptor agonist oxymetazoline (pD2 = 6.30 ± 0.22).3 The α2‐adrenoceptor antagonist yohimbine (0.01–0.1 μm, pA2 = 8.04), α2B/C‐adrenoceptor antagonist ARC 239 (10 μm, pKb = 6.33 ± 0.21), α2A/C‐adrenoceptor antagonist WB 4101 (0.3 μm, pKb = 8.01 ± 0.24), α2A‐adrenoceptor antagonists BRL44408 (0.1 μm, pKb = 6.82 ± 0.34) and RX 821002 (0.1 μm, pKb = 8.31 ± 0.35), α2C‐adrenoceptor antagonists spiroxatrine (1 μm, pKb = 7.32 ± 0.32), rauwolscine (0.1 μm, pKb = 8.16 ± 0.14) and HV 723 (0.3 μm, pKb = 7.68 ± 0.14) inhibited BHT‐920‐induced contractions in pig nasal mucosa.4 The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant α2A‐ and α2C‐adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native α2A‐ and α2C‐monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the α2B‐subtype.5 In conclusion, contractile responses to phenylephrine, BHT‐920, UK 14,304, PGE‐6201204 and oxymetazoline indicate that α1‐ and α2‐adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant α2‐adrenoceptors and native pig α2‐adrenoceptors suggest that α2A‐ and α2C‐adrenoceptor subtypes constrict pig nasal mucosa vasculature.

The bioavailability, pharmacokinetics and N-Me metabolite formation for two novel compounds in cynomolgus monkeys, designated as PGE8753474 and PGE6201204, using stable-isotope coadministration and N-in-one dosing strategies.Bioavailabilities for PGE8753474 and PGE6201204 were 9 and 19%, resp.It was also clear that PGE8753474 is more extensively metabolized, consistent with bioavailability differences, compared to PGE6201204.Urinary recovery of each compound quant. represents NMM production efficiency differences between compound types and routes of administration.