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Muscarinic receptor subtypes in airways
© INSTITUTPASTEUR/ELsEVIER Paris 1998
Res. lmmunol. 1998, 149, 201-202
Muscarinic receptor subtypes in airways EJ. Barnes
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St., SW3 6LY, London
Muscarinic receptor antagonists are the bronchodilators o f c h o i c e in the m a n a g e m e n t o f chronic obstructive pulmonary disease (COPD) and appear to be more effective that ~a-agonists [1]. They are also useful in some patients with asthma, but are less effective than inhaled 13:-agonists [2]. There have been important advances in muscarinic receptor pharmacology, with the recognition of several subtypes of muscarinic receptors in airways which appear to serve different physiological functions [3]. This has suggested that more selective muscarinic antagonists may have advantages over the existing non-selective drugs, such as ipratropium bromide and oxitropium bromide. M 1 receptors appear to be localized to parasympathetic ganglia and blockade of these receptors results in reduced reflex bronchoconstriction. The bronchoconstrictor action of acetylcholine in human airways is mediated entirely via M 3 receptors. H u m a n a i r w a y s m o o t h m u s c l e also expresses M 2 receptors, but no functional role for these receptors has been clearly defined [4]. M 2 receptors located at parasympathetic nerve terminals inhibit the release of acetylcholine, thus acting as autoreceptors [5]. Non-selective anticholinergics block M 1 and M 3 receptors, leading to bronchodilatation, as a result of relieving intrinsic cholinergic tone and inhibition of cholinergic reflex bronchoconstriction. However, by blocking prejunctional M 2 receptors, this leads to
Received April 1, 1998.
an increase in acetylcholine release and this may work against the postjunctional blockade o f M 3 receptors, making these antagonists less efficient. M 4 receptors are found in species, such as rabbit but not in humans, whereas M 5 receptors have not been demonstrated in any species. It has been difficult to develop M 3 selective a n t a g o n i s t s , but d a r i f e n c i n ( U K - 8 8 , 5 2 5 ) is reported to be M3-selective and is in clinical development [6]. A M1/M 3 selective antagonist, rispenzipine, has also been developed and does not increase acetylcholine release [5], but no clinical studies have been reported. Another M 1 / M 2 antagonist, revatropate (UK-112,166) is in clinical development as a bronchodilator for COPD [6]. The most interesting drug is tiotropium bromide (Ba 679), which has the unique property of kinetic selectivity, with rapid dissociation from M 2 receptors and slow dissociation from M 1 and M 3 receptors [7, 8]. Whether selective muscarinic antagonists will have advantages over existing non-selective drugs remains to be seen, however. The most interesting property of tiotropium bromide is its very long duration of action. It has a high affinity and dissociates very slowly from muscarinic receptors in human lung [9] and produces long-term blockade of muscarinic receptors in human airway smooth muscle [10]. This is reflected by the prolonged blockade of cholinergic neural constriction in human and guinea pig airways in vitro, with an effect lasting over 8 h in
202
P.J. B A R N E S
comparison with a duration of only one hour with ipratropium bromide. However, its effects on acetylcholine release are short-lived and similar to those seen with atropine and ipratropium bromide, thus confirming functional selectivity for M 3 compared to M 2 receptors. In clinical studies, inhaled tiotropium bromide provides long-term bronchodilatation and protection against cholinergic challenge in asthmatic subjects, with effects lasting for over 3 days [11]. In studies of patients with COPD, tiotropium bromide gives prolonged bronchodilatation, lasting over 24 h [12, 13]. This suggests that tiotropium bromide will be suitable for once daily dosing. In phase III studies, tiotropium bromide, given as a dry powder once daily, is well tolerated with no reported side effects and improves lung function in patients with COPD [14]. It is likely that this drug will become the bronchodilator of choice for long-term management of COPD, with the advantage of improved compliance with once daily dosing.
References
[1] Rennard S.I., Serby, C.W., Ghafouri, M., Johnson, P.A. & Friedman, M. (1996), Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. Chest, 110, 62-70. [2] Barnes, P.J. & Buist, A.S. (1997), The role of anticholinergics in COPD and chronic asthma. Gardner Caldwell Publications, 1-172. [3] Barnes, P.J. (1993), Muscarinic receptor subtypes in airways. Life Sci., 52, 521-528. [4] Watson, N., Magnussen, H. & Rabe K.F. 1995), Antagonism of [3-adrenoceptor-mediated relaxations
of human bronchial smooth muscle by carbachol. Eur..L Pharrnacol., 275, 307-310. [5] Patel, H.J., Barnes, P.J., Takahashi, T., Tadjkarimi, S., Yacoub, M.H., Belvisi, M.G. (1995), Characterization of prejunctional nmscarinic autoreceptors in human and guinea-pig trachea in vitro. Am. J. Resp. Crit. Care Med., 152, 872-878. [6] Alabaster, V.A. (1997), Discovery and development of selective M 3 antagonists for clinical use. Life Sci., 60, 1053-1060. [7] Disse, B., Reichal, R., Speck, G., Travnecker, WW., Rominger, K.L., Hammer, R. (1993), Ba 679 BR, a novel anticholinergic bronchodilator: preclinical and clinical aspects. Life Sci., 52, 537-544. [8] Barnes, P.J., Belvisi, M.G., Mak, J.C.W., Haddad, E. & O'Connor, B. (1995), Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci., 56, 853-859. [9] Haddad, E., Mak, J.C.W. & Barnes, P.J. (1994), Characterization of [3H]Ba 679, a slow-dissociating musc~xinic receptor antagonist in human lung: radioligand, binding and autoradiographic mapping. Mol. PharmacoL, 45, 899-907. [10] Takahashi, T., Belvisi, M.G., Patel, H. et al. (1994), Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea-pig and human airways. Am. J. Resp. Crir Care Med., 150, 1640-1645. [11] O'Connor, B.J., Towse, L.J. & Barnes, P.J. (1996), Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am. J. Respir Crit. Care Med., 154, 876-880. [12] Maesen, F.P.V., Smeets, J.J., Costongs, M.A.L., Wald, F.D.M. & Cornelissen, P.J.G. (1993), BA 679 Br, a new long-acting antimuscarinic bronchodilator; a pilot dose escalation study. Eur. Resp. J., 6, 1031-1036. [13] Maesen, F.P.V., Smeets, J.J., Sledsens, T.M.J., Wald, F.D.M., Cornelissen, J.P.G. (1995), Tiotropium bromide, a new long-acting antimuscarinic bronchodilatot: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Eur. Respir J., 8, 1506-1513. [14] Littner, M., Auerbach, D., Campbell, S. et al. (1997), The bronchodilator effects of tiotropium bromide in stable COPD. Am. J. Respir. Crir Care Med., 155, A282.
Res. lmmunol. 1998, 149, 201-202
Muscarinic receptor subtypes in airways EJ. Barnes
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St., SW3 6LY, London
Muscarinic receptor antagonists are the bronchodilators o f c h o i c e in the m a n a g e m e n t o f chronic obstructive pulmonary disease (COPD) and appear to be more effective that ~a-agonists [1]. They are also useful in some patients with asthma, but are less effective than inhaled 13:-agonists [2]. There have been important advances in muscarinic receptor pharmacology, with the recognition of several subtypes of muscarinic receptors in airways which appear to serve different physiological functions [3]. This has suggested that more selective muscarinic antagonists may have advantages over the existing non-selective drugs, such as ipratropium bromide and oxitropium bromide. M 1 receptors appear to be localized to parasympathetic ganglia and blockade of these receptors results in reduced reflex bronchoconstriction. The bronchoconstrictor action of acetylcholine in human airways is mediated entirely via M 3 receptors. H u m a n a i r w a y s m o o t h m u s c l e also expresses M 2 receptors, but no functional role for these receptors has been clearly defined [4]. M 2 receptors located at parasympathetic nerve terminals inhibit the release of acetylcholine, thus acting as autoreceptors [5]. Non-selective anticholinergics block M 1 and M 3 receptors, leading to bronchodilatation, as a result of relieving intrinsic cholinergic tone and inhibition of cholinergic reflex bronchoconstriction. However, by blocking prejunctional M 2 receptors, this leads to
Received April 1, 1998.
an increase in acetylcholine release and this may work against the postjunctional blockade o f M 3 receptors, making these antagonists less efficient. M 4 receptors are found in species, such as rabbit but not in humans, whereas M 5 receptors have not been demonstrated in any species. It has been difficult to develop M 3 selective a n t a g o n i s t s , but d a r i f e n c i n ( U K - 8 8 , 5 2 5 ) is reported to be M3-selective and is in clinical development [6]. A M1/M 3 selective antagonist, rispenzipine, has also been developed and does not increase acetylcholine release [5], but no clinical studies have been reported. Another M 1 / M 2 antagonist, revatropate (UK-112,166) is in clinical development as a bronchodilator for COPD [6]. The most interesting drug is tiotropium bromide (Ba 679), which has the unique property of kinetic selectivity, with rapid dissociation from M 2 receptors and slow dissociation from M 1 and M 3 receptors [7, 8]. Whether selective muscarinic antagonists will have advantages over existing non-selective drugs remains to be seen, however. The most interesting property of tiotropium bromide is its very long duration of action. It has a high affinity and dissociates very slowly from muscarinic receptors in human lung [9] and produces long-term blockade of muscarinic receptors in human airway smooth muscle [10]. This is reflected by the prolonged blockade of cholinergic neural constriction in human and guinea pig airways in vitro, with an effect lasting over 8 h in
202
P.J. B A R N E S
comparison with a duration of only one hour with ipratropium bromide. However, its effects on acetylcholine release are short-lived and similar to those seen with atropine and ipratropium bromide, thus confirming functional selectivity for M 3 compared to M 2 receptors. In clinical studies, inhaled tiotropium bromide provides long-term bronchodilatation and protection against cholinergic challenge in asthmatic subjects, with effects lasting for over 3 days [11]. In studies of patients with COPD, tiotropium bromide gives prolonged bronchodilatation, lasting over 24 h [12, 13]. This suggests that tiotropium bromide will be suitable for once daily dosing. In phase III studies, tiotropium bromide, given as a dry powder once daily, is well tolerated with no reported side effects and improves lung function in patients with COPD [14]. It is likely that this drug will become the bronchodilator of choice for long-term management of COPD, with the advantage of improved compliance with once daily dosing.
References
[1] Rennard S.I., Serby, C.W., Ghafouri, M., Johnson, P.A. & Friedman, M. (1996), Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. Chest, 110, 62-70. [2] Barnes, P.J. & Buist, A.S. (1997), The role of anticholinergics in COPD and chronic asthma. Gardner Caldwell Publications, 1-172. [3] Barnes, P.J. (1993), Muscarinic receptor subtypes in airways. Life Sci., 52, 521-528. [4] Watson, N., Magnussen, H. & Rabe K.F. 1995), Antagonism of [3-adrenoceptor-mediated relaxations
of human bronchial smooth muscle by carbachol. Eur..L Pharrnacol., 275, 307-310. [5] Patel, H.J., Barnes, P.J., Takahashi, T., Tadjkarimi, S., Yacoub, M.H., Belvisi, M.G. (1995), Characterization of prejunctional nmscarinic autoreceptors in human and guinea-pig trachea in vitro. Am. J. Resp. Crit. Care Med., 152, 872-878. [6] Alabaster, V.A. (1997), Discovery and development of selective M 3 antagonists for clinical use. Life Sci., 60, 1053-1060. [7] Disse, B., Reichal, R., Speck, G., Travnecker, WW., Rominger, K.L., Hammer, R. (1993), Ba 679 BR, a novel anticholinergic bronchodilator: preclinical and clinical aspects. Life Sci., 52, 537-544. [8] Barnes, P.J., Belvisi, M.G., Mak, J.C.W., Haddad, E. & O'Connor, B. (1995), Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci., 56, 853-859. [9] Haddad, E., Mak, J.C.W. & Barnes, P.J. (1994), Characterization of [3H]Ba 679, a slow-dissociating musc~xinic receptor antagonist in human lung: radioligand, binding and autoradiographic mapping. Mol. PharmacoL, 45, 899-907. [10] Takahashi, T., Belvisi, M.G., Patel, H. et al. (1994), Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea-pig and human airways. Am. J. Resp. Crir Care Med., 150, 1640-1645. [11] O'Connor, B.J., Towse, L.J. & Barnes, P.J. (1996), Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am. J. Respir Crit. Care Med., 154, 876-880. [12] Maesen, F.P.V., Smeets, J.J., Costongs, M.A.L., Wald, F.D.M. & Cornelissen, P.J.G. (1993), BA 679 Br, a new long-acting antimuscarinic bronchodilator; a pilot dose escalation study. Eur. Resp. J., 6, 1031-1036. [13] Maesen, F.P.V., Smeets, J.J., Sledsens, T.M.J., Wald, F.D.M., Cornelissen, J.P.G. (1995), Tiotropium bromide, a new long-acting antimuscarinic bronchodilatot: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Eur. Respir J., 8, 1506-1513. [14] Littner, M., Auerbach, D., Campbell, S. et al. (1997), The bronchodilator effects of tiotropium bromide in stable COPD. Am. J. Respir. Crir Care Med., 155, A282.