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Copyright © 2004 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2004, 56, 499508 ISSN 1230-6002 “…I’ll tell you all my ideas about Looking Glass House. First, there’s the room you can see through the glass – that’s just the same as our drawing room, only the thing go other way… Well then, the books are something like our books, only the words go the wrong way; …I wonder if they’d give you milk in there? Perhaps Looking-Glass milk isn’t good to drink…” “Through the Looking Glass” Lewis Caroll (1832–1898) REVIEW INFLUENCE OF THE ABSOLUTE CONFIGURATION ON PHARMACOLOGICAL ACTIVITY OF ANTIHYPERTENSIVE AND ANTIARRHYTHMIC DRUGS Katarzyna Kulig, Piotr Nowicki, Barbara Malawska Department of Pharmaceutical Chemistry, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland Influence of the absolute configuration on pharmacological activity of antihypertensive and antiarrhythmic drugs. K. KULIG, P. NOWICKI, B. MALAWSKA. Pol. J. Pharmacol., 2004, 56, 499–508. Chirality is a fundamental property of biological systems and reflects the underlying asymmetry of matter. Interactions of drugs with receptors, en- zymes or binding sites have long been known to be stereoselective, and it is increasingly recognized that both pharmacodynamic and pharmacokinetic events contribute to the overall clinically observed stereoselectivity. The pharmacological activity may reside only in one enantiomer, while the second one may be inactive or have desirable or undesirable activity. Two isomers may be nearly identical both in qualitative and quantitative as- pects of pharmacological activity. The activity of particular enantiomers may differ only at the quantitative level. It is also possible that a particular enan- tiomer displays qualitatively different mode of action than the second one. This review describes the influence of the absolute configuration on pharmacological activity of the selected currently used or being under inves- tigation drugs acting on cardiovascular system, especially as the antihyper- tensive and antiarrhythmic agents. Key words: chirality, absolute configuration, antihypertensive drugs, an- tiarrhythmic agents correspondence; e-mail: mfmalaws@cyf-kr.edu.pl K. Kulig, P. Nowicki, B. Malawska Introduction in potency between enantiomers, whereas weakly active compounds had little difference between Isomers are unique molecular entries composed enantiomers. The enantiomer with the highest ac- of the same molecular constituents with common tivity is termed after Ariëns the eutomer, while the structural characteristics. Among several subtypes one with the lowest is distomer. The eutomer/dis- of isomers, optical isomers are said to possess a “chi- tomer ratio is called the eudismic ratio [10, 21]. ral” or asymmetrical center. Term “chiral” derives Only one enantiomer may be responsible for the from the Greek term chiros meaning hand, and de- pharmacological activity of chiral drug. In this scribes a molecule, which is not superimposable on case, the other enantiomer is regarded as an inac- its mirror image (Fig. 1). The chirality fascinated tive or undesirably active impurity. Two optical scientists since the middle of 19th century, when isomers may have nearly identical both qualitative Louis Pasteur presented optical isomers of tartaric and quantitative pharmacological activity or their acid. By picking the differing crystal types, he re- activity can differ only quantitavely. Additionally, cognized that any of optical isomers polarized light an enantiomer could display adverse pharmacol- differently, and by extending this idea, the concept ogical activity [21, 38]. Differences in the activity of an asymmetrical atom was proposed by van’t of stereoisomers may be also shown in terms of Hoff and Le Bel in 1874 [5, 25]. their bioavailability, distribution, metabolic and Life and chirality are strictly connected. At a mo- elimination behavior, and can be seen everywhere, lecular level, chirality represents an intrinsic pro- where stereochemical parameters have fundamen- perty of the ‘building blocks of life’, such as amino tal significance to their action and disposition in acids, sugars, peptides, proteins and polysaccha- biological systems [17, 28, 48, 50]. rides. As a result, metabolic and regulatory pro- In this review, we present only a brief overview cesses occurring in biological systems are sensitive of different pharmacological response to selected to stereochemistry and different responses may be enantiomeric cardiovascular drugs and compounds observed when comparing the activities of enanti- being under investigation as cardiovascular agents. omers [28]. Taking the above into consideration, Its aim is illustration of potential benefits and/or enantiomeric drugs have became increasingly im- danger of using a single enantiomer in therapy of portant over the last 20–30 years. The advanced hypertension and arrhythmia. technology let synthesize enantiomerically pure Cardiovascular diseases are a reason of about compounds. In parallel, it is of interest to replace 50% of premature death in Western industrialized a drug already approved as racemate by its more countries, and, therefore, an extensive search for active enantiomer, so call ‘chiral switches’. In new and better drugs became a challenge for differ- 2001, of the $ 410 billion in worldwide sales of for- ent pharmaceutical laboratories both industrial and mulated pharmaceutical products $ 147 billion be- academic [47]. longs to single-enantiomer drugs [4, 38, 49]. Theoretical description of interaction between Adrenoceptor antagonists an enantiomer and a biological system was formu- lated by Carl Pfeiffer. He observed that highly po- Adrenoceptor (AR) antagonists are mainly used tent chiral compounds showed a larger difference for treating angina and hypertension. Agents which block the a-ARs act on the a-ARs of blood vessels, causing relaxation of smooth muscles, dilatation of mirror the blood vessels, and drop in blood pressure. A A Agents which block the b -ARs act on the b-ARs in the heart slowing down the heart rate and reducing the force of contractions. b-Blockers also have a range of other effects in other parts of body which D B B D contribute to decrease of blood pressure [14, 39]. C C a-Adrenoceptor antagonists Prazosin, the prototype of quinazoline-bearing compounds, was the first a-AR antagonist used as Fig. 1. Mirror image of a hypothetical chiral molecule an effective agent in the treatment of hypertension. 500 Pol. J. Pharmacol., 2004, 56, 499–508 THE ABSOLUTE CONFIGURATION OF DRUGS Its pharmacological activity depends on peripheral racemic mixture and enantiomers. However, in case vasodilatation mediated by a post-junctional a-AR of a -AR, the binding affinity of (S)-doxazosin was blockade. Additionally, prazosin improves the plasma slightly lower than that of (R) enantiomer. Addi- lipid profile [22, 51, 52]. Being an achiral com- tionally, (S)-doxazosin exhibited a higher a/a -AR pound, prazosin became a very useful and interest- selectivity ratio (480–612) as compared to the (R) ing lead compound in developing new antihyper- isomer (107–140). The racemic mixture showed in- tensive agents (Fig. 2). The replacement of the termediate selectivity between its component enan- piperazine ring with decahydroquinoxaline moiety tiomers [13]. leads to optically active, potent and selective (a/ Also compounds bearing benzodioxane ring a ratio 1800) prazosin analog, cyclazosin (Fig. 2). substituted at the 2-position display affinity for It was shown that (-)-cyclazosin, although more po- a-AR. The model compound of this series WB tent than (+)-cyclazosin at all subtypes of a-AR, 4101 (Fig. 3) is highly potent towards a-AR, and was nearly devoid, like parent compound, of retains significant affinity for other receptor sys- a-AR subtype selectivity, with the exception of tems such as a -AR and 5-HT) receptors. Its enan- a 12-fold higher affinity for native a* vs. a)-AR. tiomers have different affinities for a-AR. The In addition, (+)-cyclazosin displayed high affinity (S)-WB 4101 has been reported to be much more (pKE = 9.16) for cloned a*-AR and a significantly active than the corresponding (R) enantiomer, and lower potency at both a*- and a,-ARs (pKE = their affinities for a)-AR are 0.16 and 39.8 nM, 7.48 and 7.57, respectively). Additionaly, (+)-cycla- respectively [2, 32]. zosin displays selectivities of 1100-, 19000- and Among several analogues of WB 4101, me- 12000-fold in binding to a*-AR vs. a -AR, phendioxan, bearing p-tolyl substituent at 3-position 5-HT) and D -receptors, respectively [32, 33]. is the most potent and selective for a-AR sub- The role of the furan moiety of prazosin was in- types. (-)-Mephendioxan was significantly more vestigated through its replacement by various rings. active at a-AR than the other optic isomer. This The compound bearing 1,4-benzodioxane ring, enantiomer was also 12000-, 2500-, 250-fold more doxazosin (Fig. 2), displayed affinity for a -AR, selective in binding to a-AR relative to a -AR, and is used for treatment of hypertension and be- 5-HT) and D -receptors, respectively [32]. nign prostate hyperplasia (BHP). In the radioligand b binding studies using an isolated human tissue, -Adrenoceptor antagonists doxazosin and its enantiomers showed higher affin- The b-blockers comprise a group of drugs that ity for a-AR than a -AR, but no significant differ- is mostly used to treat cardiovascular disorders, ences in affinity for a-AR were observed between such as hypertension, cardiac arrhythmia or ische- O O N CH O N N 3 N Prazosin CH3O NH2 O O O O N N CH O N N 3 CH O N N O 3 N CH O N 3 CH O (S)-Doxazosin 3 (+)-Cyclazosin NH 2 NH 2 Fig. 2. Prazosin and its chiral analogs ISSN 1230-6002 501 K. Kulig, P. Nowicki, B. Malawska X R H CO 3 Metoprolol is a selective antagonist of b1-AR, and is used as a racemate. Its b-blocking capacity NH has been shown to reside predominantly in the O O (S)-enantiomer, whereas (R)-enantiomer does not WB 4101 X = O,R=H OCH contribute to this effect.