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(−)‐Discretamine, a selective α 1D ‐adrenoceptor antagonist, isolated from Fissistigma glaucescens
Author(s) -
Ko FengNien,
Guh JihHwa,
Yu SheuMeei,
Hou YuSheng,
Wu YangChang,
Teng CheMing
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13207.x
Subject(s) - prazosin , vas deferens , phenylephrine , antagonist , nifedipine , competitive antagonist , endocrinology , medicine , chemistry , contraction (grammar) , pharmacology , biology , receptor , calcium , blood pressure
1 The selectivity of (−)‐discretamine for α 1 ‐adrenoceptor subtypes was investigated by use of functional and binding studies in rat vas deferens, spleen and aorta, and in cultured DDT 1 MF‐2 and A10 cells. 2 In prostatic portions of rat vas deferens, the competitive antagonists (−)‐discretamine, 5‐methyl‐urapidil (5‐MU) and prazosin inhibited contractions to noradrenaline (NA) with pA 2 values of 6.21, 8.71 and 9.27, respectively. The irreversible antagonist, chloroethylclonidine (CEC, 100 μ m ) failed to affect contractions to NA while nifedipine (1 μ m ) blocked them almost completely. 3 In rat spleen, the competitive antagonists (−)‐discretamine, 5‐MU and prazosin inhibited contractions to phenylephrine with pA 2 values of 6.44, 7.19 and 9.45, respectively. CEC (100 μ m ) significantly reduced the maximum contraction to phenylephrine while nifedipine (1 μ m ) did not affect it. 4 In rat aorta, the competitive antagonists (−)‐discretamine, 5‐MU and prazosin inhibited contractions to NA with pA 2 values of 7.60, 8.00 and 9.40, respectively. CEC also antagonized the contractions to NA in a competitive manner with a pA 2 value of 6.10. 5 The specific binding of [ 3 H]‐prazosin to DDT 1 MF‐2 and A10 cells was concentration‐dependent and saturated at 3–5 nM with K D values of 0.24 ± 0.02 and 0.20 ± 0.02 nM, respectively. (−)‐Discretamine, 5‐MU, CEC and prazosin inhibited specific [ 3 H]‐prazosin binding to DDT 1 MF‐2 and A10 cells in a concentration‐dependent manner with IC 50 values of 390.8 ± 20.6, 43.6 ± 3.9, 200.0 ± 30.0 and 0.8 ± 0.1 nM, respectively in DDT 1 MF‐2 cells, and 25.0 ± 3.2, 8.6 ± 1.4, 1000.0 ± 30.8 and 0.52 ± 0.03 nM, respectively in A10 cells. 6 Pretreatment of A10 cells with CEC (10 μ m ) for 30 min and then washed out thoroughly, reduced specific [ 3 H]‐prazosin binding by 30%. The CEC‐insensitive [ 3 H]‐prazosin binding was inhibited by (−)‐discretamine with an IC 50 value of 7.0 ± 0.3 nM. 7 5‐MU (100 nM), CEC (1 μ m ) and prazosin (10 nM) markedly inhibited NA (3 μ m )‐induced [ 3 H]‐inositol monophosphate formation in DDT 1 MF‐2 and A10 cells, while (−)‐discretamine (100 nM) inhibited NA‐induced [ 3 H]‐inositol monophosphate formation only in A10 cells. 8 In conclusion, (−)‐discretamine is a selective α 1D ‐adrenoceptor antagonist in vascular smooth muscle. Its selectivity among various α 1 ‐adrenoceptor subtypes is α 1A :α 1B :α 1D = 0.04:0.07:1.0.