Skip to main content
Log in

Comparison of the α-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine and corynanthine

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

In the present studies the potency and selectivity of idazoxan (RX 781094) were compared with yohimbine and its diastereoisomers rauwolscine and corynanthine in both functional studies and radioligand binding experiments. Prejunctional α2- and postjunctional α1-adrenoceptor antagonist potencies were assessed by determining pA2 values against clonidine on the stimulated rat vas deferens and noradrenaline on the anococcygeus muscle, respectively. The rank order of prejunctional α2-adrenoceptor antagonist potency was idazoxan > yohimbine > rauwolscine ≫ corynanthine. At postjunctional α1-adrenoceptors the rank order of antagonist potency was rauwolscine > corynanthine > yohimbine > idazoxan. The selectivity values (α21) for idazoxan, yohimbine, rauwolscine and corynanthine were 245, 45, 3 and 0.03 respectively. The selectivity and potency profiles established for these antagonists in functional studies were confirmed in radioligand binding studies utilising 3H-idazoxan (α2) and 3H-prazosin (α1) in rat cerebral cortex.

In pithed rats intravenously administered idazoxan, yohimbine and rauwolscine fully reversed the inhibitory effects of clonidine on electrically-induced contractions of the vas deferens; idazoxan was approximately ten times more potent than both yohimbine and rauwolscine. Corynanthine was inactive. Idazoxan and yohimbine also fully antagonised the inhibitory effects of guanabenz on electrically-induced contractions of the anococcygeus muscle; idazoxan again was more than ten times more potent than yohimbine in this model. The inhibitory effects of guanabenz were less readily antagonised by rauwolscine indicating that the selectivity of this compound is less than that of yohimbine in this tissue. Corynanthine was again inactive.

Studies were also undertaken in which the effects of an extended range of antagonists were examined on contractions of the anococcygeus muscle induced either by electrical stimulation or intra-arterial phenylphrine. Selective α1-adrenoceptor antagonists produced a parallel block of the effects of stimulation and phenylephrine indicating that the postjunctional receptor in this tissue is predominantly α1- character. In this tissue idazoxan potentiated nerve stimulation without inhibiting phenylephrine responses; of the compounds studied only idazoxan failed to influence phenylephrine responses.

Under the present experimental conditions idazoxan only produced antagonist properties at α-adrenoceptors and consistently displayed improved α2-selectivity and potency with respect to yohimbine and rauwolscine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 14:48–58

    Google Scholar 

  • Broadhurst A, Ennis C, Lattimer N (1983) Paradoxical agonist effect of phentolamine. Br J Pharmacol 78: 149P

  • Chapleo CB, Doxey JC, Myers PL, Roach AG (1981) RX 781094 a new potent, selective antagonist of α2-adrenoceptors. Br J Pharmacol 74: 842P

  • Cheng YC, Prusoff NH (1973) Relationship between the inhibition constant (K i) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Google Scholar 

  • Dettmar PW, Lynn AG, Tulloch IF (1983) Neuropharmacological studies in rodents on the action of RX 781094, a new selective α2-adrenoceptor antagonist. Neuropharmacology 22:729–739

    Google Scholar 

  • Doxey JC (1979) Pre- and postsynaptic effects of α-agonists in the anococcygeus muscle of pithed rats. Eur J Pharmacol 54:185–189

    Google Scholar 

  • Doxey JC, Everitt JE (1977) Inhibitory effects of clonidine on responses to sympathetic nerve stimulation in the pithed rat. Br J Pharmacol 61:559–566

    Google Scholar 

  • Doxey JC, Easingwood RE (1978) Profiles of α-adrenoceptor antabonists in the pithed rat. Br J Pharmacol 63: 401P

  • Doxey JC, Roach AG (1980) Presynaptic α-adrenoreceptors; In vitro methods and preparations utilised in the evaluation of agonists and antagonists. J Auton Pharmacol 1:73–99

    Google Scholar 

  • Doxey JC, Gadie B, Lane AC, Tulloch IF (1983a) Evidence for pharmacological similarity between Neuropharmacological studies in rodents on the action of RX 781094, a new selective α2-adrenoceptors in the vas deferens and central nervous system of the rat. Br J Pharmacol 80:155–161

    Google Scholar 

  • Doxey JC, Roach AG, Smith CFC (1983b) Studies on RX 781094: a selective, potent and specific antagonist, of α2-adrenoceptors. Br J Pharmacol 78:489–505

    Google Scholar 

  • Flockhart JR, Haynes MJ, Walters DS (1982) RX 781094 increases the α-mpt-induced rate of decline of noradrenaline of rat cortex. Br J Pharmacol 76 [Proc Suppl]: 236P

  • Gadie B, McCarthy PS, Tulloch IF (1983) Analysis of cortical EEG synchronisation induced by clonidine in the conscious rabbit. Br J Pharmacol 80 [Proc Suppl]: 652P

  • Goldstein JM, Knobloch LC, Malick JB (1983) Electrophysiological demonstration of both α2-agonist and antagonist properties of RX 781094. Eur. J Pharmacol 91: 101–105

    Google Scholar 

  • Grant JA, Scrutton MC (1979) Novel α2-adrenoceptors primarily responsible for inducing human platelet aggregation. Nature 277:659–661

    Google Scholar 

  • Hedler L, Stamm G, Weitzell R, Starke K (1981) Functional characterisation of central α-adrenoceptors by yohimbine diastereoisomers. Eur J Pharmacol 70:43–52

    Google Scholar 

  • Kobinger W, Pichler L (1981) 143-7 subtypes: selectivity of various agonists and relative distribution of receptors as determined in rats. Eur J Pharmacol 73:313–321

    Google Scholar 

  • Lane AC, Howlett DR, Walter DS (1983) The effects of metal ions on the binding of a new α2-adrenoceptor antagonist radioligand (3H)-RX 781094 in rat cerebral cortex. Biochem Pharmacol 32:3122–3125

    Google Scholar 

  • Langer SZ, Pimoule C, Scatton B (1983) (3H)-RX 781094, a preferential α2-adrenoceptor antagonist radioligand, labels, α2-adrenoceptors in the rat brain cortex. Br J Pharmacol 78 [Proc Suppl]: 109P

  • Lattimer N, Rhodes KF, Ward TJ, Waterfall JF, White JF (1982) Selective α2-adrenoceptor activity of novel substituted benzoquinolizines. Br J Pharmacol 75 [Proc Suppl]:154P

  • Madjar H, Docherty JR, Starke K (1980) An examination of pre- and postsynaptic α-adrenoceptors in the autoperfused rabbit hindlimbs. J Cardiovasc Pharmacol 2:619–627

    Google Scholar 

  • Marshall I, Nasmyth PA, Shepperson NB (1977) Presynaptic α-adrenoceptors and the inhibition by uptake blocking agents of the twitch response of the mouse vas deferens. Br J Pharmacol 59:511P

    Google Scholar 

  • Marwaha J, Aghajanian GK (1982) Relative potencies of alpha-1 and alpha-2 antagonists in the locus coeruleus, dorsal raphe and dorsal lateral geniculate nuclei: An electrophysiological study. J Pharmacol Exp Ther 222:287–293

    Google Scholar 

  • Michel AD, Whiting RL (1981) 2-(2-imidazolyl methyl)-1,4-benzodioxans, a series of selective α2-adrenoceptor antagonists. Br J Pharmacol 74:255–256P

    Google Scholar 

  • Mouille P, Dabire H, Fournier B, Schmitt H (1981) A further attempt to characterise the α2-adrenoceptor blocking properties of (imidazolyl-2-)-2-benzodioxane 1–4 (170, 150) in pithed rats. Eur J Pharmacol 73:367–370

    Google Scholar 

  • Paciorek PM, Shepperson NB (1983) 144-3 agonist activity of 144-4 antagonists in the pithed rat preparation. Br J Pharmacol 79:12–14

    Google Scholar 

  • Roach AG, Doxey JC, Berridge TL (1983a) Mechanism of pressor reponses to RX 781094, a selective α2-adrenoceptor antagonist, in pithed rats. Fed Proc 42, 636 [Abst] 2014

    Google Scholar 

  • Roach AG, Doxey JC, Strachan DA, Cavero I (1983b) Sleeping times evoked by alpha adrenoceptor agonists in two day old chicks: An experimental model to evaluate full and partial agonists of central alpha-2-adrenoceptors J Pharmacol Exp Ther 227:421–428

    Google Scholar 

  • Rockhold RW, Gross F (1981) Yohimbine diastereoisomers: Cardiovascular effects after central and peripheral application in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 315:227–231

    Google Scholar 

  • Scatton B, Zivkovic B, Dedek J (1980) Antidopaminergic properties of yohimbine. J Pharmacol Exp Ther 215:494–499

    Google Scholar 

  • Scatton B, Dedek J, Zivkovic B (1983) Lack of involvement of α2-adrenoceptors in the regulation of striatal dopaminergic transmission. Eur J Pharmacol 86:427–433

    Google Scholar 

  • Shepperson NB, Duval N, Massingham R, Langer SZ (1981) Pre-and postsynaptic alpha adrenoceptor selectivity studies with yohimbine and its two diastereoisomers rauwolscine and corynanthine in the anaesthetised dog. J Pharmacol Exp Ther 219:540–546

    Google Scholar 

  • Starke K, Montel H (1973) Involvement of α-receptors in clonidine-induced inhibition of transmitter release from central monoamine neurones. Neuropharmacology 12:1073–1080

    Google Scholar 

  • Tanaka T, Starke K (1980) Antagonist/agonist-preferring α-adrenoceptors of α12-adrenoceptors. Eur J Pharmacol 63:191–194

    Google Scholar 

  • Tayo FM (1982) Agonist action of yohimbine on the perfused rabbit central ear artery. Blood Vessels 19:197–202

    Google Scholar 

  • Timmermans PBMWM, Schoop AMC, Kwa HY, van Zwieten PA (1981) Characterisation of α-adrenoceptors participating in the central hypotensive and sedative effects of clonidine using yohimbine, rauwolscine and corynanthine. Eur J Pharmacol 70:7–15

    Google Scholar 

  • Van Rossum JM (1963) Cumulative dose-response curves. II. Techniques for making dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther 143:299–329

    Google Scholar 

  • Waldmeier PC, Bischoff S (1981) Interaction of α-agonists and antagonists with dopaminergic transmission. Experientia 37:677

    Google Scholar 

  • Weitzell R, Tanaka T, Starke K (1979) Pre- and postsynaptic effects of yohimbine stereoisomers on noradrenergic transmission in the pulmonary artery of the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 308:127–136

    Google Scholar 

  • Whittaker V (1969) The synaptosome, handbook of neurochemistry, vol 2. Plenum Press, London, pp 327–364

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Doxey, J.C., Lane, A.C., Roach, A.G. et al. Comparison of the α-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine and corynanthine. Naunyn-Schmiedeberg's Arch. Pharmacol. 325, 136–144 (1984). https://doi.org/10.1007/BF00506193

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00506193

Key words

Navigation