Relationships between structure and vascular activity in a series of benzylisoquinolines

Abstract

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.

Synthesis of N-Substituted Piperazinyl Carbamoyl and Acetyl Derivatives of Tetrahydropapaverine: Potent Antispasmodic Agents.

“…[2][3][4][5][6] Because of these multiple mechanisms it is useful as a non-specific spasmolytic agent but cannot be put to more specific use in cardiovascular and abdominal disorders. 7) However, if we take the chemical structure of papaverine as a model, we may find that small structural differences could lead to more useful compounds.…”

Evaluation and synthesis of 7-arylhydroxymethyltriazolopyridines as potential cardiovascular agents

“…In the context of our work on synthesis and reactivity of [1,2,3]triazolo[1,5-a]pyridines 1 and 2, 5 we have studied lithiation reactions that are regioselective at the 7 position. The 7-lithio derivatives are formed at -40ºC and can be trapped by electrophiles.…”

“…Some aporphine alkaloids have been also reported to have a relaxant effect on vascular smooth muscle that is also related to their capacity to inhibit Ca +2 influx through voltage-operated Ca +2 channels or to block α 1 -adrenoceptors. [1][2][3][4] The search for new compounds with activity in vascular pathologies is an interesting challenge, considering that these conditions are the major cause of death in the European Community. The idea that 7-arylhydroxymethyltriazolopyridines might be considered as structural analogues of the above mentioned compounds led us to synthesize a series of these triazolopyridine derivatives and to carry out a preliminary evaluation of them as cardiovascular agents.…”

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Abstract 7-Arylhydroxymethyltriazolopyridines 3a-c and 4a-d were synthesized by regioselective lithiation of [1,2,3]triazolo[1,5-a]pyridines 1 and 2 and subsequent trapping of the 7-lithioderivatives formed using aryl aldehydes as electrophiles. The structural relationship between compounds 3a-c and 4a-d and arylethanolamines suggested their consideration as potential cardiovascular agents.

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Synthesis and antispasmodic effect of aryl substituted N-carbamoyl/thiocarbamoyl isoquinolines

“…Clinically, papaverine is employed as a vasodilator because of its relaxatory effect on vascular smooth muscle 8,9 . Few N-acyl derivatives of papaverine and related compounds show variety of activities against AIDS, glucoma and fungal infections [10][11][12] . In quest for biologically more potent compounds we envisioned to synthesize aryl substituted N-carbamoyl as well as N-thiocarbamoyl derivatives of tetrahyropapaverine.…”