(−)‐Discretamine, a selective α_1D‐adrenoceptor antagonist, isolated from Fissistigma glaucescens

Abstract

1 The selectivity of (-)-discretamine for al-adrenoceptor subtypes was investigated by use of functional and binding studies in rat vas deferens, spleen and aorta, and in cultured DDTIMF-2 and AlO cells. 2 In prostatic portions of rat vas deferens, the competitive antagonists (-)-discretamine, 5-methylurapidil (5-MU) and prazosin inhibited contractions to noradrenaline (NA) with pA2 values of 6.21, 8.71 and 9.27, respectively. The irreversible antagonist, chloroethylclonidine (CEC, 100 tiM) failed to affect contractions to NA while nifedipine (1 jaM) blocked them almost completely.3 In rat spleen, the competitive antagonists (-)-discretamine, 5-MU and prazosin inhibited contractions to phenylephrine with pA2 values of 6.44, 7.19 and 9.45, respectively. CEC (100I1M) significantly reduced the maximum contraction to phenylephrine while nifedipine (1 jaM) did not affect it.4 In rat aorta, the competitive antagonists (-)-discretamine, 5-MU and prazosin inhibited contractions to NA with pA2 values of 7.60, 8.00 and 9.40, respectively. CEC also antagonized the contractions to NA in a competitive manner with a pA2 value of 6.10. Its selectivity among various al-adrenoceptor subtypes is a1A:a1B:aE1D =0.04:0.07:1.0.

The effects of SB 216469, an antagonist which discriminates between the α1A‐adrenoceptor and the human prostatic α1‐adrenoceptor

“…Therefore, the second aim of this study was to investigate whether the CXIA-adrenoceptor selectivity of SB 216469 also translates into selectivity in functional tests. For this purpose we have used well established models of MIAadrenoceptors (rat vas deferens, Burt et al, 1995; anococcygeus muscle, Mir & Fozard, 1988), alB-adrenoceptors (rat spleen, Burt et al, 1995; guinea-pig aorta, Mir & Fozard, 1988, and MID-adrenoceptors (rat aorta, Ko et al, 1994;Kenny et al, 1995). The affinities obtained in these functional systems were in excellent agreement with those obtained at the cloned rat aladrenoceptor subtypes, and the value obtained at the rat aortic alD-adrenoceptor is in close agreement with that found by Testa et al (1994).…”

“…Radioligand binding studies were performed in rat tissues (spleen, liver, cerebral cortex and kidney) and with cloned a,-adrenoceptor subtypes, the actions of SB 216469 being compared with the known CXA-adrenoceptor-selective reference compound (+)-niguldipine (Boer et al, 1989). To investigate subtype-selectivity at functional receptors, studies were performed on isolated tissues: rat vas deferens and anococcygeus muscle which posses IIA-adrenoceptors (Mir & Fozard, 1988;Burt et al, 1995), rat spleen and guinea-pig aorta where responses are mediated via alB-adrenoceptors (Mir & Fozard, 1988;Burt et al, 1995) and rat aorta where LID-adrenoceptors mediate contraction (Ko et al, 1994;Kenny et al, 1995). The potency of SB 216469 at these receptors has been compared with that obtained at the al-adrenoceptors of human isolated prostatic strips.…”

A possible structural determinant of selectivity of boldine and derivatives for the α1A‐adrenoceptor subtype

“…To date, the data on the a,-adrenoceptor subtypes present in rat aorta are confusing. Although some studies have suggested that the al-adrenoceptor population is a homogeneous entity which has been postulated to be either aIA (Beckering & Brodde, 1989), a1B (Eltze & Boer, 1992;Testa et al, 1995), non-calA/non-oxlB (Oriowo & Ruffolo, 1992;Aboud et al, 1993), ,ID (Ko et al, 1994), or 'predominantly' 21D , others have suggested that a number of different subtypes contribute to the contractile response in rat aorta ; Van der Graaf et al, 1996). Moreover, Rokosh et al (1994) andPiascik et al (1994) reported that they could detect mRNA for the alb, al, and dLd adrenoceptors in the rat aorta.…”

Functional evidence equating the pharmacologically‐defined α1A‐ and cloned α1C‐adrenoceptor: studies in the isolated perfused kidney of rat

“…Currently, however, the cloned alc-adrenoceptor, which exhibits high affinity for 5-methyl-urapidil, WB 4101, oxymetazoline and S(+)-niguldipine, is also considered to be the same receptor as theaA-adrenoceptor described pharmacologically above Faureet al, 1994;Clarke et al, 1994;Price et al, 1994;Michel & Insel, 1994). The clonedalD-adrenoceptor, characterized by its low affinity for 5-methyl-urapidil, oxymetazoline and (+ )-niguldipine and its relative resistance to alkylation by CEC, is without a clear-cut functional correlate , although the a,-adrenoceptor mediating contraction of the rat aorta in vitro is claimed as an xlD-adrenoceptor (Ko et al, 1994;Saussy et al, 1994).…”