Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application

Abstract

The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.

Keywords: Papaver somniferum; SARS-CoV-2; alkaloid; anticancer; antiviral; benzylisoquinoline; opium; papaverine.

Figure 1

Structure of papaverine.

Figure 2

Similar compounds of papaverine helped to elucidate the structure of papaverine.

Figure 3

The NH pathway of papaverine synthesis. TYDC = tyrosine decarboxylase, TyrAT = L-tyrosine aminotransferase, 4HPPDC = 4-hydroxyphenylpyruvate decarboxylase, 3OHase = tyramine 3-hydroxylase, NCS = norcoclaurine synthase, 6OMT = norcoclaurine-6-O-methyltransferase, 3’OHase = 3’ hydroxylase, 3’OMT = 3′-O-methyltransferase, 4’OMT = 3′-hydroxy-N-methylcoclaurine 4′-O-methyltransferase, 7OMT = norreticuline 7-O-methyltransferase, DBOX = dihydrobenzophenanthridine oxidase.

Figure 4

The NCH₃ pathway of papaverine synthesis. 6OMT = norcoclaurine-6-O-methyltransferase, CNMT = coclaurine-N-methyltransferase, NMCH = (S)-N-methylcoclaurine 3′-hydroxylase, 4’OMT = 4′-O-methyltransferase, 7OMT = reticuline 7-O-methyltransferase, 3’OMT = 3′-O-methyltransferase, LNdeMT = laudanosine N-demethylase, DBOX = dihydrobenzophenanthridine oxidase.

Figure 5

Mechanism of action of papaverine in smooth muscle relaxation. Smooth muscle contraction requires five steps: After the increase in intracellular Ca²⁺ concentration from the extracellular fluid, these ions bind to a protein called calmodulin (CaM). This complex activates a protein called myosin light-chain kinase (MLCK) (papaverine inhibits this step), which subsequently phosphorylates light chains of myosin heads, increasing the myosin ATPase activity. Finally, active myosin cross-bridges slide along actin and create muscle tension to contract the cell.

Figure 6

Mechanism of action of papaverine in relaxation of cavernosal smooth muscle. Papaverine blocks cAMP and cGMP phosphodiesterase to raise the concentration of cAMP and cGMP, which further releases MLCP that dephosphorylates myosin, resulting in smooth muscle relaxation and increased cGMP that activates PKG and leads to smooth muscle relaxation (1). Activated PKG lowers Ca²⁺ influx. Ca²⁺ activates MLCK, which contracts smooth muscle via myosin phosphorylation (2). Papaverine induces efflux of K+ with subsequent hyperpolarization and relaxation of corpora cavernosa smooth muscle cells.