RELATIONSHIPS BETWEEN STRUCTURE AND VASCULAR ACTIVITY IN A SERIES OF BENZYLISOQUINOLINES

1. In the present work, the properties of 3-methyl isoquinoline, 3,4-d ihydropapaverine, tetrahydropapaverine and tetrahydropapaveroline were compared with those of papaverine and laudanosine. The work includes functional studies on rat isolated aorta contracted with noradrenaline , caffeine or KC1, and a determination of the affinity of the compound s for alpha(1)-adrenoceptors and calcium channel binding sites, with [ H-3]-prazosin, [H-3]-nitrendipine and [H-3]-(+)-cis-diltiazem binding to rat cerebral cortical membranes. The effects of papaverine derivati ves on the different molecular forms of cyclic nucleotide phosphodiest erases (PDE) isolated from bovine aorta were also determined. 2. The t hree papaverine derivatives show greater affinity than papaverine for the [H-3]-prazosin binding site. They are therefore more selective as inhibitors of [H-3]-prazosin binding as opposed to [H-3]-(+)-cis-dilti azem, while papaverine appears to have approximately equal affinity fo r both. [H-3]-nitrendipine binding was not affected by either papaveri ne or papaverine derivatives in concentrations up to 100 mu M. 3-Methy lisoquinoline had no effect on any of the binding sites assayed. 3. Co ntractions evoked by noradrenaline (1 mu M) in rat aorta were inhibite d in a concentration-dependent manner by 3,4-dihydropapaverine, tetrah ydropapaverine and with a lower potency, by tetrahydropapaveroline. In Ca2+-free solution, tetrahydropapaverine and to a lesser extent, tetr ahydropapaveroline, inhibited the noradrenaline (1 mu M) evoked contra ction in a concentration-dependent manner and did not modify the phasi c contractile response evoked by caffeine (10 mu M). This suggests tha t these alkaloids do not act at the intracellular level, unlike papave rine which inhibits the contractile response to caffeine and noradrena line. 4. Inositol phosphates formation induced by noradrenaline (1 mu M) in rat aorta was inhibited by tetrahydropapaverine. (100 mu M) and tetrahydropapaveroline (300 mu M), thus suggesting that alpha(1D)-adre noceptors are coupled to phosphoinositide metabolism in rat aorta. 5. Unlike papaverine, which has a significant effect on all the PDE isofo rms, the three alkaloids assayed did not have an inhibitory effect on the different forms of PDE isolated from bovine aorta. 6. These result s provide evidence that papaverine derivatives with a partially or tot ally reduced isoquinoline ring have a greater affinity far alpha(1)-ad renoceptors and a lower affinity for benzothiazepine sites in the Ca2-channel than papaverine. This structural feature also implies a loss of the inhibitory activity on PDE isoforms. The planarity of the isoqu inoline ring (papaverine) impairs the interaction with the alpha(1)-ad renoceptor site and facilitates it with the Ca2+-channels and PDEs, wh ereas the more flexible tetrahydroisoquinoline ring increases the bind ing to alpha(1)-adrenoceptors.