Relationships between structure and vascular activity in a series of benzylisoquinolines.
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, caffeine or KCl, and a determination of the affinity of the compounds for alpha1-adrenoceptors and calcium channel binding sites, with [3H]-prazosin, [3H]-nitrendipine and [3H]-(+)-cis-diltiazem binding to rat cerebral cortical membranes. The effects of papaverine derivatives on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were also determined. 2. The three papaverine derivatives show greater affinity than papaverine for the [3H]-prazosin binding site. They are therefore more selective as inhibitors of [3H]-prazosin binding as opposed to [3H]-(+)-cis-diltiazem, while papaverine appears to have approximately equal affinity for both. [3H]-nitrendipine binding was not affected by either papaverine or papaverine derivatives in concentrations up to 100 microM. 3-Methylisoquinoline had no effect on any of the binding sites assayed. 3. Contractions evoked by noradrenaline (1 microM) in rat aorta were inhibited in a concentration-dependent manner by 3,4-dihydropapaverine, tetrahydropapaverine and with a lower potency, by tetrahydropapaveroline. In Ca2+-free solution, tetrahydropapaverine and to a lesser extent, tetrahydropapaveroline, inhibited the noradrenaline (1 microM) evoked contraction in a concentration-dependent manner and did not modify the phasic contractile response evoked by caffeine (10 mM). This suggests that these alkaloids do not act at the intracellular level, unlike papaverine which inhibits the contractile response to caffeine and noradrenaline. 4. Inositol phosphates formation induced by noradrenaline (1 microM) in rat aorta was inhibited by tetrahydropapaverine (100 microM) and tetrahydropapaveroline (300 microM), thus suggesting that alpha1D-adrenoceptors are coupled to phosphoinositide metabolism in rat aorta. 5. Unlike papaverine, which has a significant effect on all the PDE isoforms, the three alkaloids assayed did not have an inhibitory effect on the different 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 affinity for alpha1-adrenoceptors 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 isoquinoline ring (papaverine) impairs the interaction with the alpha1-adrenoceptor site and facilitates it with the Ca2+-channels and PDEs, whereas the more flexible tetrahydroisoquinoline ring increases the binding to alpha1-adrenoceptors.
Chulia
S
S
Departamento de Farmacologia, Facultad de Farmacia, Universidad de Valencia, Spain.
Ivorra
M D
MD
Martinez
S
S
Elorriaga
M
M
Valiente
M
M
Noguera
M A
MA
Lugnier
C
C
Advenier
C
C
D'Ocon
P
P
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004110:Diltiazem / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010208:Papaverine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
D007295:Inositol Phosphates; D007546:Isoquinolines; D010276:Parasympatholytics; C001522:laudanosine; D010208:Papaverine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D004110:Diltiazem; D011224:Prazosin