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Home , Imidazoline receptor, Rilmenidine

JOURNAL FÜR HYPERTONIE

BOUSQUET P I1 imidazoline receptors: From the pharmacological basis to the therapeutic application

Journal für Hypertonie - Austrian Journal of 2002; 6 (Sonderheft 4), 6-9

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were “hybrid”, i.e. they bound not pancreas. Ongoing research in this a NTRODUCTION only to 2- receptors and exciting field is designed to achieve I a sometimes 1-adrenergic receptors this end. The remainder of this up- but also to specific, nonadrenergic date will be devoted solely to descri- Imidazolines and similar centrally imidazoline receptors. This was bing advances made concerning acting drugs are antihypertensive particularly true in the case of cloni- receptors involved in the regulation

agents that inhibit the activity of the dine [4–6]. Products belonging to the of sympathetic tone, namely I1-imida- orthosympathetic nervous system [1]. latest generation – including rilmeni- zoline receptors [11]. Their site of action is located in the dine, the leading compound – exhibit

central nervous system, more specifi- a certain selectivity for nonadrenergic I1-imidazoline receptors have been cally in the medulla oblongata; i.e. receptors; compared with , identified in several different species, in the lateral reticular nucleus of the their selectivity has been approxi- and in several different tissues, organs rostroventral medulla [2]. Imidazoli- mately 3 to 10 times greater for and cell lines. We have shown that a nes and related hypotensive substan- imidazoline receptors than for 2- they are present at a fairly high densi- ces are highly effective drugs. How- adrenergic receptors [7]. Hence, this ty in the region of the medulla oblon- ever, the first generation frequently means that, although selective, some gata which contains the site of hypo- had bothersome adverse effects, binding to adrenergic receptors does tensive action for imidazoline-like although they were generally not occur. However, shows and related drugs. We also demon- very severe. Pharmacologists and sufficiently poor affinity and weak strated that they were located on the a pharmaceutical chemists interested activity at 2-adrenergic receptors for plasma membrane of neurons. in these drugs had to answer at least side effects associated with the activa- a two important questions: tion of 2-adrenergic receptors to be Various teams have made attempts to l What is the pharmacological me- adequately diminished in terms of clone the receptors. For the moment, chanism underlying the hypoten- both frequency and severity compared these have not been entirely success- sive action of these drugs? with the earlier generation of drugs. ful, probably because the l From a mechanistic point of view, This is notably true in the case of the protein is unstable in the case of would it be possible to differentia- sedative effect, dryness of the mucous attempts that require purification of te the hypotensive effect from the membranes, bradycardia and even the receptor, and because the mole- most common adverse effect, i.e. the rebound effect which is not obser- cular tools are not sufficiently selec- sedation? ved with rilmenidine [1]. tive in the case of attempted cloning that relies on expression. New cloning Nevertheless, using these tools, it was strategies are being developed. There possible to distinguish two or even are several experimental arguments three subtypes of imidazoline recep- in favour of coupling the receptor to MECHANISM OF ACTION tors. Subtype I1, involved in cardio- one or more G proteins. Two mecha- vascular effects, is sensitive to cloni- nisms of signal transduction associ-

dine and (an antagonist of ated with I1-imidazoline receptors It was established very early on that central antihypertensive effects) have recently been identified: phos-

imidazolines and molecules with whereas subtype I2 is insensitive to phatidylcholine-sensitive phospho- imidazoline-like structures were able clonidine but sensitive to idazoxan. lipase C and adenyl cyclase [12, 13].

to lower blood pressure by an effect The I2- was iden- on their site of action in the medulla, tified as a site for Much information has already been

although and phenyl- regulation [8, 9]. As for subtype I3, it obtained concerning I1-imidazoline ethylamines were incapable of produ- is currently the most puzzling recep- receptors. However, ligands which cing such an effect at the same site tor; its existence was suggested on would only bind to and therefore [3]. This structure-activity relation- the basis of functional studies which only act upon these receptors –

ship factor showed that activation of demonstrated that certain imidazo- specifically ignoring alpha2-adre- alpha-adrenergic receptors was not lines exerted a regulatory action on nergic receptors – have been sadly the prime mechanism of this action. the pancreatic secretion of . lacking not only for use in the conti- On the basis of this, the existence of These pharmacological effects fail to nued analysis of this nonadrenergic a nonadrenergic receptor specifically correspond with the pharmacology receptor system but also for the

acted upon by imidazolines was of either I1- or I2-imidazoline recep- exploration of potential new thera- suggested. The identification and tors [10]. However, it has so far been peutic pathways which would rely biochemical characterization of impossible to detect any nonadre- exclusively on such a system. these receptors were delayed by the nergic specific binding of imidazo- fact that all the available ligands line-like or related compounds in the

6 J. HYPERTON. Sonderheft 4/2002

For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. I1-IMIDAZOLINE RECEPTORS: FROM THE PHARMACO- LOGICAL BASIS TO THE THERAPEUTIC APPLICATION

The synthesis of pyrroline analogues of imidazolines and reference oxazo- Table 1: Affinities (Ki ± s.e.m (nM)) lines led to an appreciable increase a a 1AR 2AR I1R in selectivity for I1-receptors compa- a LNP 509 >10 000 > 10 000 538 ± 163 red with 2 and I2. A few of these compounds will be mentioned: S23515 1.710 ± 474 > 10 000 6.40 ± 1.94 S23515, S23757, LNP 509 and S23757 > 10 000 > 10 000 5.30 ± 1.48 LNP911. Table 1 indicates the affini- LNP 911 > 10 000 > 10 000 0.2 ± 0.1 ties of these compounds for I1-, I2- and a -adrenergic receptors and their the hypotensive effect of a purely persists in D79N mice; in this case, 2 a a selectivity ratios [14–16]. 2-, -methylnor- the synergistic interaction induced in [14]. normal animals only by the “hybrid” These compounds are the first imida- drug, rilmenidine, cannot occur in zoline analogues described which More recently still, we synthesized D79N mice. It is evident from these are devoid of any significant affinity other imidazoline, oxazoline and data that rilmenidine represents a valu- a for 2-adrenergic receptors, and we pyrroline analogues which also proved able compromise between its neces- have confirmed that they do not to be highly selective for imidazoline sary activity at imidazoline receptors a exhibit any agonist or antagonist receptors and had even greater affi- and sufficiently weak 2-adrenergic activity at these receptors. Some of nity for the latter. Hence, they are activity so that it has few adverse these compounds have allowed us to powerful tools which can already be effects at the recommended doses but answer one crucial question concer- used for the further exploration and is adequate to trigger the synergistic ning this research topic: are imidazo- identification of these original recep- interaction which is responsible for line analogues which are totally with- tors, and especially for further attempts its marked hypotensive effect. It is out effect on adrenergic receptors at cloning, as well as in “drug design” therefore an interesting drug for capable of affecting blood pressure? strategies [15]. normalizing blood pressure in most In fact, we recently reported that of hypertensive patients. compounds S23515 and LNP509 Since several experimental findings induce a dose-dependent hypoten- appeared to indicate that imidazo- sive effect in the anaesthetized rabbit line and a-adrenergic systems might when they are administered directly interact in the central regulation of in the vicinity of the medulla oblon- cardiovascular function and the ADDITIONAL EFFECTS gata, i.e. intracisternally [14, 17]. action of hybrid drugs, we put this These drugs do not cross the blood- hypothesis to the test using these brain barrier and must be injected new molecular tools. Thus, the The centrally acting antihypertensive directly into the brain. We showed sequential administration of a low drugs, such as rilmenidine, have that LNP509 is as active in geneti- dose of LNP509, without any intrinsic remarkable antiarrhythmic effects in cally modified D79N mice (whose effect, followed 10 minutes later by a experimental models of ventricular a a 2-adrenergic receptors have under- dose of -methylnoradrenaline with arrhythmia associated with sympa- gone mutation so that they are no very little effect in the anaesthetized thetic hyperactivity [18]. They are longer functional) as in wild-type rabbit produced a very marked effect also capable of producing an appre- mice (i.e. those having normally on blood pressure. The drugs were ciable improvement in haemodyna- a functioning 2-adrenergic receptors) administered intracisternally in these mic parameters in models of left [17]. experiments, a-methylnoradrenaline ventricular dysfunction (certain forms being used as the reference “pure” of chronic heart failure). Some have a From now on, similar products 2-adrenergic agonist. As expected, a beneficial effect on survival in the which cross the blood-brain barrier this synergistic interaction was not models previously mentioned [19]. a and can therefore be administered found in D79N mice whose 2- Such additional effects are extremely systemically are also available. adrenergic receptors are non interesting and need to be confirmed, S23757, which has no intrinsic effect functional [17]. particularly in man. Clinical trials are on blood pressure when used under being worked out with the aim of the same experimental conditions, Interestingly, the central hypotensive achieving this. Some drugs which are totally inhibits the hypotensive action effect of rilmenidine is only obtained selective for imidazoline receptors of S23515 and LNP509; it is the first at high doses in the D79N mouse retain these cardiac activities, and it antagonist which is truly selective and the effect is less pronounced than should therefore be possible to deve- towards imidazoline receptors; it has in control wild-type mice. Only the lop drugs that are well tolerated: no inhibitory effect whatsoever on imidazoline receptor-linked effect l antihypertensive agents with addi-

J. HYPERTON. Sonderheft 4/2002 7 I1-IMIDAZOLINE RECEPTORS: FROM THE PHARMACO- LOGICAL BASIS TO THE THERAPEUTIC APPLICATION

tional cardiac effects, antihypertensive agents, the develop- lipids and insulin concentrations. In l antiarrhythmics at non hypotensi- ment of drugs with greater selectivity addition, as noted in experimental ve doses, for imidazoline receptors led to a animal models, in patients showing a l drugs that can be used in the tre- considerable decrease in the inci- metabolic syndrome associated with atment of heart failure at non hy- dence and severity of adverse effects hypertension, sympathetic overacti- potensive doses. [1]. Rilmenidine is foremost among vity and hyperinsulinism, rilmeni- such effective, well tolerated anti- dine even significantly lowered the hypertensive drugs and it has under- plasma fasting and 2-hour glucose Renal imidazoline-specific binding gone extensive clinical study. In levels and plasma insulin concentra- sites have also been described [20]. addition to its good safety profile, its tion after an oral glucose tolerance A direct effect of rilmenidine was antihypertensive efficacy has been test. This result shows the specific observed in the rabbit as well as in deemed equivalent to that of drugs potential value of sympathoinhibi- the human kidney, where it inhibits belonging to other major classes of tory drugs in treating this common the Na+/H+ exchanger. This effect drugs routinely employed in the disease. was contrary to the one induced by treatment of essential hypertension: a the activation of renal 2-adrenocep- diuretics, beta-blockers, As had already been suggested by a tors [21]. Rilmenidine was shown to angiotensin converting enzyme few open trials involving small increase renal blood flow, potassium inhibitors, and calcium channel groups of patients, the echocardio- excretion, natriuresis associated with blockers (figure 1). graphic results from a recent study inhibition of sodium reabsorption, carried out on a larger number of and diuresis, whereas the sympathetic Trials have shown that rilmenidine subjects were analyzed blind and renal nerve activity was markedly may be used in combination with showed that rilmenidine significantly decreased [22]. An attractive hypo- other antihypertensives so as to decreased left ventricular mass in thesis would be that these effects increase the efficacy of treatment hypertensive patients with left ventri- explain the absence of any water or without particularly increasing the cular hypertrophy. Another (pilot) sodium retention in chronic treat- risk of adverse effects (for review see study conducted in non insulin-depen- ments of hypertensive patients with [1, 26]). dent diabetic patients with micro- rilmenidine, and account for long albuminuria showed that rilmenidine term benefits of the drug. Several open or controlled clinical was as effective as captopril not only trials demonstrated that rilmenidine in lowering blood pressure but also Imidazoline-related drugs are capable does not affect plasma glucose, plasma in reducing microalbuminuria. of decreasing the glucose-induced insulin secretion from pancreatic b- cells [23–25]. This effect seems to be Figure 1. Controlled randomized comparative studies rilmenidine versus other specific for imidazoline compounds; major classes of drugs (De Luca N et al. J Hypertens 2000; 18: 1515–22. it could not be reproduced with non- Scemama M et al. J Cardiovasc Pharmacol 1995; 26 (suppl 2): S34–S39. imidazoline a-adrenoceptor agonists. Dallochio M et al. Ach Mal Coeur Vaiss 1991; 84 (suppl): 42. Fiorentini C et It was suggested that this action al. Arch Mal Coeur Vaiss 1989; 82 (suppl): 39–46. Luccioni R. Presse Med could involve receptors specific for 1995; 24: 1857–64). imidazolines but different from the

classic I1 or I2-binding sites.

THERAPEUTIC VALUE

The adverse effects of first generation imidazolines – the most common being the sedative effect – were clearly a related to their ability to activate 2- adrenergic receptors whereas their hypotensive action primarily involves a nonadrenergic mechanism. In the case of second generation central

8 J. HYPERTON. Sonderheft 4/2002 I1-IMIDAZOLINE RECEPTORS: FROM THE PHARMACO- LOGICAL BASIS TO THE THERAPEUTIC APPLICATION

6. Ernsberger P, Meeley MP, Mann JJ, Reis DJ. Imidazoline Receptors. Mol Pharmacol 2002; Clonidine binds to imidazole binding sites as 62: 181–91. CONCLUSION a well as 2-adrenoceptors in the ventrolateral 17. Bruban V, Estato V, Schann S, Ehrhardt JD, medulla. Eur J Pharmacol 1987; 134: 1–13. Monassier L, Renard P, Scalbert E, Feldman J, a 7. Bricca G, Dontenwill M, Molines A, Bousquet P. Evidence for synergy between 2- A great many new facts have recently Feldman J, Tibirica E, Belcourt A, Bousquet P. adrenergic and nonadrenergic mechanisms in come to light concerning both the Rilmenidine selectivity for imidazoline central blood pressure regulation. Circulation mechanism of action and clinical receptors in human brain. Eur J Pharmacol 2002; 105: 1116–21. efficacy of imidazoline-like drugs. 1989; 163: 373–7. 18. Roegel JC, Yannoulis N, De Jong W, New pharmacological tools and mo- 8. Parini A, Coupry I, Graham RM, Uzielli I, Feldman J, Bousquet P. Preventive effect of dern animal models have made it Atlas D, Lanier SM. Characterization of an rilmenidine on the occurrence of neurogenic imidazoline/guanidinium receptive site ventricular arrhythmias in rabbits. J Hypertens possible to develop compounds that a distinct from the 2-. J Biol 1998; 16 (suppl 3): S39–S43. are highly selective towards specific Chem 1989; 264: 11874–8. 19. Thomas L, Gasser B, Bousquet P, nonadrenergic imidazoline receptors 9. Limon I, Coupry I, Lanier SM, Parini A. Monassier LJ. Haemodynamic and cardiac which, in turn, has led to the resolu- Purification and characterization of antihypertrophic actions of clonidine in tion of important questions: mitochondrial imidazoline-guanidinium Goldblatt 1K-1C rats. Cardiovasc Pharmacol l the activation of I -imidazoline re- receptive site from rabbit kidney. J Biol Chem 2002; in press. 1 1992; 267: 21645–9. ceptors in the medulla oblongata 20. Coupry I, Podevin RA, Dausse JP, Parini A. 10. Morgan NG, Chan SL. Imidazoline Evidence for imidazololine binding sites in is by itself sufficient to alter blood binding sites in the endocrine pancreas: can basolateral membranes from rabbit kidney. pressure; they fulfil their potential as targets for the Biochem Biophys Res Commun 1987; 147: l the imidazolinergic system and development of new insuline secretagogues? 1055–60. a Curr Pharm Res 2001; 14: 1413–31. 2-adrenergic system act synergi- 21. Limon I, Coupry I, Lanier SM, Parini A. stically in the processes of regula- 11. Heemskerk FMJ, Dontenwill M, Vonthron Purification and characterization of ting vasomotor sympathetic tone; C, Bousquet P. [125I]para-iodoclonidine reveals mitochondrial imidazoline-guanidinium a new subtype of imidazoline specific sites in receptive site from rabbit kidney. J Biol Chem l a the residual 2-adrenergic activity synaptosomal plasma membranes of the 1992; 267: 21645–9. of rilmenidine is enough for it to bovine brainstem. J Neurochem 1998; 71: 22. Kline RL, Cechetto DF. Renal effects of exert this synergistic effect but 2193–202. Rilmenidine in anaesthetized rats: importance also sufficiently weak for rilmeni- 12. Separovic D, Kester M, Haxhiu MA, of renal nerves. J Pharmacol Ther 1993; 266: dine to be much better tolerated Ernsberger P. Activation of phosphatidyl- 1556–62. choline-selective phospholipase C by I - than first generation drugs. 1 23. Chan SLF, Brown CA, Scarpello KE, imidazoline receptors in PC12 cells and Morgan NB. The imidazoline site involved in rostral ventrolateral medulla. Brain Res 1997; control of insulin secretion: characteristics 749: 335–9. that distinguish it from I1 and I2 sites. Br J 13. Greney H, Ronde P, Magnier C, Maranca Pharmacol 1994; 112: 1065–70. F, Rascente C, Quaglia W, Gianella M, Pigini 24. Plant TD, Henquin JC. and M, Brasili L, Lugnier C, Bousquet P, inhibit ATP-sensitive K+ channels References: Dontenwill M. Coupling of I1-imidazoline in mouse pancreatic b-cells. Br J Pharmacol 1. Bousquet P, Feldman J. Drugs acting on receptors to the cAMP pathway: studies with 1990; 101: 115–20. imidazoline receptors: a review of their a highly selective , benazoline. Mol clinical pharmacology, their use in blood Pharmacol 2000; 57: 1142–51. 25. Chan SLF, Dunne MJ, Stillings MR, Morgan NG. The a adrenoceptor antagonist pressure control and their potential interest in 2- 14. Bruban V, Feldman J, Greney H, + cardioprotection. Drugs 1999; 58: 799–812. modulates K ATP channels in Dontenwill M, Schann S, Jarry C, Payard M, insulin-secreting cells. Eur J Pharmacol 1991; 2. Bousquet P, Feldman J, Bloch R, Schwartz J. Boutin J, Scalbert E, Pfeiffer B, Renard P, 204: 41–8. The nucleus reticularis lateralis: a region Vanhoutte P, Bousquet P. Respective highly sensitive to clonidine. Eur J Pharmacol contribution of a-adrenergic and non- 26. Reid JL. Update on rilmenidine: clinical 1981; 69: 389–92. adrenergic mechanisms in the hypotensive benefits. Am J Hypertension 2001; 14: 322S– 324S. 3. Bousquet P, Feldman J, Schwartz J. Central effect of imidazoline-like drugs. Br J cardiovascular effects of a-adrenergic drugs: Pharmacol 2001; 133: 261–6. difference between catecholamines and 15. Schann S, Bruban V, Pompermayer K, imidazolines. J Pharmacol Exp Ther 1984; Feldman J, Pfeiffer B, Scalbert E, Bousquet P, 230: 232–6. Ehrhardt JD. Synthesis and biological evalua- 4. Bricca G, Dontenwill M, Molines A, tion of pyrrolinic isosteres of rilmenidine. Feldman J, Belcourt A, Bousquet P. The Discovery of cis/trans-Dicyclopropyl methyl- imidazoline preferring receptors: binding (4,5-dimethyl –,(-dihydro-3H-pyrrol-2-yl)- Korrespondenzadresse: studies in bovine, rat and human brainstem. amine (LNP 509), an I1 imidazoline receptor Prof. Dr. Pascal Bousquet Eur J Pharmacol 1989; 62: 1–9. selective ligand with hypotensive activity. J Laboratoire de Neurobiologie et Med Chem 2001; 44: 1588–93. 5. Bricca G, Greney H, Zhang J, Dontenwill Pharmacologie Cardiovasculaire M, Stutzmann J, Belcourt A, Bousquet P. 16. Greney H, Urosevic D, Schann S, Dupuy Université Louis Pasteur L, Bruban V, Ehrhardt JD, Bousquet P, Human brain imidazoline receptors: Further Strasbourg, France characterization with [3H]clonidine. Eur J Dontenwill M. [(125)I]2-(2-Chloro-4-iodo- Pharmacol-Molec Pharmacol Sect 1994; 266: phenylamino)-5-methyl-pyrroline (LNP 911), a E-mail: pascal.bousquet@ 25–33. high-affinity radioligand selective for I1 medicine.u-strasbg.fr

J. HYPERTON. Sonderheft 4/2002 9 Mitteilungen aus der Redaktion

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