1 The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9-0-methylboldine) and glaucine (2,9-0-dimethylboldine) on 5 These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectivity of action for the aIA-adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2-hydroxy function, induces a significant increase in aCIA-subtype selectivity and affinity.

No abstract

The contractile responses obtained by activation of different muscarinic receptor subtypes in the longitudinal muscle of the rat ileum and especially the responses of this muscle to acetylcholine in a Ca(2+)-free medium have been investigated. In Ca(2+)-containing solution, acetylcholine elicited similar concentration-dependent contractile responses in the duodenum, jejunum and ileum strips of the rat intestine. The response to a maximal concentration of the agonist (1 microM) consisted of a rapid phasic response followed by a slower tonic one. Nifedipine completely relaxes or inhibits the sustained response and only partially diminishes the phasic one, which suggests that the phasic contraction depends on the release of internal Ca2+ entry from the extracellular space through voltage-dependent Ca2+ channels, but that the tonic contraction only depends on the influx of the external ion. In Ca(2+)-free medium, acetylcholine (1 microM) induced phasic contractions that depend on the release of this ion from internal stores. Participation of different subtypes of receptors (M1, M2 and M3) in these responses depends on the inhibitory action shown by methoctramine, 4-DAMP and atropine but not by pirenzepine in two different experimental models.

1 In the present work, the properties of 3-methyl isoquinoline, 3,4-dihydropapaverine, tetrahydropapaverine and tetrahydropapaveroline were compared with those of papaverine and laudanosine. The work includes functional studies on rat isolated aorta contracted with noradrenaline, ca eine or KC1, and a determination of the a nity of the compounds for a 1 -adrenoceptors and calcium channel binding sites, with 3 Contractions evoked by noradrenaline (1 mM) in rat aorta were inhibited in a concentrationdependent manner by 3,4-dihydropapaverine, tetrahydropapaverine and with a lower potency, by tetrahydropapaveroline. In Ca 2+ -free solution, tetrahydropapaverine and to a lesser extent, tetrahydropapaveroline, inhibited the noradrenaline (1 mM) evoked contraction in a concentration-dependent manner and did not modify the phasic contractile response evoked by ca eine (10 mM). This suggests that these alkaloids do not act at the intracellular level, unlike papaverine which inhibits the contractile response to ca eine and noradrenaline. 4 Inositol phosphates formation induced by noradrenaline (1 mM) in rat aorta was inhibited by tetrahydropapaverine (100 mM) and tetrahydropapaveroline (300 mM), thus suggesting that a 1D -adrenoceptors are coupled to phosphoinositide metabolism in rat aorta. 5 Unlike papaverine, which has a signi®cant e ect on all the PDE isoforms, the three alkaloids assayed did not have an inhibitory e ect on the di erent forms of PDE isolated from bovine aorta. 6 These results provide evidence that papaverine derivatives with a partially or totally reduced isoquinoline ring have a greater a nity for a 1 -adrenoceptors and a lower a nity for benzothiazepine sites in the Ca 2+ -channel than papaverine. This structural feature also implies a loss of the inhibitory activity on PDE isoforms. The planarity of the isoquinoline ring (papaverine) impairs the interaction with the a 1 -adrenoceptor site and facilitates it with the Ca 2+ -channels and PDEs, whereas the morē exible tetrahydroisoquinoline ring increases the binding to a 1 -adrenoceptors.

The action of 1S,1'S-tetrandrine, a bisbenzyltetrahydroisoquinoline alkaloid, on alpha1-adrenoceptors has been compared with that of its isomer 1R,1'S-isotetrandrine. The work includes binding assays to analyse the affinity of these products for the [3H]prazosin binding site of rat cerebral cortical membranes and functional studies on rat isolated aorta to examine the effects of both alkaloids on intracellular calcium processes related or not to alpha-adrenoceptor activation. A radioligand receptor-binding study showed that both compounds interacted with the alpha1-adrenoceptors displacing [3H]prazosin from the specific binding site. The Ki values (inhibition constants) were 0.69+/-0.12 and 1.6+/-0.4 microM for tetrandrine and isotetrandrine, respectively. The functional studies showed that both alkaloids concentration-dependently inhibited noradrenaline-induced contraction in Ca2+-free solution (IC50 values, i.e. the concentrations needed to induce 50% inhibition, were 252.8 and 174.9 microM for tetrandrine and isotetrandrine, respectively), the spontaneous contractile response elicited by extracellular calcium after depletion of noradrenaline-sensitive intracellular stores (increase in resting tone; IC50 values 11.6 and 19.6 microM for tetrandrine and isotetrandrine, respectively) and the refilling of intracellular Ca2+ stores sensitive to noradrenaline (IC50 values 7.4 and 14.9 microM for tetrandrine and isotetrandrine, respectively). The results show that tetrandrine and isotetrandrine interact with alpha1-adrenoceptors by displacing the [3H]prazosin binding site and that both compounds inhibit mainly the Ca2+-dependent process and have less action on alpha1-adrenoceptors. Tetrandrine is more potent than isotetrandrine.