- Email: [email protected]
The histamine H3 receptor : pharmacology and potential therapeutic applications
ANAPHYLACTOID RISK IN ANAESTHESIA
(~ Masson, Paris. Ann Fr Anesth Reanim, 12:114-115, 1993
The histamine Ha receptor: pharmacology and potential therapeutic applications Le troisi me r6cepteur de I'histamine" pharmacologie et applications th6rapeutiques potentielles M. GARBARG, J.C. SCHWARTZ Unit6 de Neurobiologie et Pharmacologie (U. 109) de I'INSERM, Centre PauI-Broca, 2 ter, rue d'Alesia, 75014 Paris
RI~SUM#: R6cemment, nous avons montr6 dans le cerveau l'existence d'un troisi~me r6cepteur de l'histamine (HA), dont la pharmacologie est clairement diff6rente de celledes r6cepteurs HI et H2- C'est un autor6cepteur port6 par le neurone histaminergique lui-m6me, qui r6gule la synth~se et la lib6ration de I'HA par un processus de r6troaction n6gative. Un puissant agoniste [(R)a-m6thylhistamine] et un puissant antagoniste (thiop6ramide) de ce r6cepteur ont 6t6 synth6tis6s. Ils ont une affinit6 n6gligeable pour les r6cepteurs H 1 et 1-12,Ces deux compos6s p6nbtrent dans le cerveau et peuvent modifier la vitesse de renouvellement de I'HA neuronale de faqon oppos6e. Comme I'HA est une amine d'6veil, l'antagoniste des r6cepteurs H3 pourrait augmenter la vigilance, alors que l'agoniste aurait des effets s6datifs. Les effecteurs des r6cepteurs H 3 sont aussi pr6sents sur des neurones non histaminergiques. Le r6cepteur H 3 exerce aussi des fonctions inhibitrices dans des tissus p6riph6riques. I1 a ainsl 6t6 mis en 6vldence dans l'appareil respiratoire ofi il inhibe la biosynth~se d'HA dans les mastocytes. De plus la (R)u-m6thylhistamine inhibe les contractions de la bronche humaine isol6e, prodmtes par stimulation 61ectrique du vague ainsi que la lib6ration des m6diateurs peptidergiques h partir des fibres C sensitives. L'identification du troisi~me r6cepteur de I'HA et des r6ponses mhibitrices vari6es, qu'induit sa stimulation dans divers organes, sugg~re des perspectives th6rapeutiques_
T h e actions o f h i s t a m i n e ( H A ) w e r e b e l i e v e d to b e m e d i a t e d b y o n l y two subclasses of r e c e p t o r s , H1 a n d H2, until t h e d i s c o v e r y of a t h i r d class o f H A r e c e p t o r s in t h e c e n t r a l n e r v o u s s y s t e m which differs f r o m t h e o t h e r t w o b y its p h a r m a c o l o g y . It has b e e n n a m e d H3 [5]. Initially, H 3 r e c e p t o r s w e r e i d e n t i f i e d as p r e s y n a p t i c a u t o r e c e p t o r s m o d u lating the synthesis a n d r e l e a s e o f H A via a n e g a tive f e e d b a c k p r o c e s s . H o w e v e r , e v i d e n c e has b e e n o b t a i n e d d r a w i n g t h a t H3 r e c e p t o r s a r e also l o c a t e d on n o n h i s t a m i n e r g i c n e u r o n s in t h e b r a i n as well as in p e r i p h e r a l tissues.
Ha RECEPTORS IN THE CENTRAL NERVOUS SYSTEM: DESIGN OF SELECTIVE AGONISTS AND ANTAGONISTS
In 1983, it was s h o w n that H A inhibits its o w n d e p o l a r i s a t i o n - i n d u c e d r e l e a s e via s t i m u l a t i o n o f
Presented at the meeting ~ New Trends in Anaphylactoid Risk in Anaesthesia ~. Nancy (France), 11-12 June 1992_
p r e s y n a p t i c r e c e p t o r s in b r a i n slices [1] H i g h l y p o t e n t a n d selective H 3 ligands w e r e d e v e l o p e d in c o l l a b o r a t i o n with t h e l a b o r a t o r i e s o f W . S c h u n a c k ( U n i v e r s i t y o f B e r l i n , G e r m a n y ) , M. R o b b a ( U n i versity of C a e n , F r a n c e ) a n d C . R . G a n e l l i n ( U n i versity C o l l e g e , L o n d o n , U K ) . T h e p r o t o t y p i c agonist is t h e chiral agonist ( R ) a - m e t h y l H A , after which (R)e~,(S)13-dimethylHA was d e v e l o p e d (pr Schunack). More recently, imetit (imidazolylethylis o t h i o u r e a ) was i d e n t i f i e d as a p o t e n t H 3 r e c e p t o r a g o n i s t (Pr G a n e l l i n ) . T h e s e t h r e e c o m p o u n d s a r e highly p o t e n t a n d selective, b e i n g a l m o s t d e v o i d of a n y action o n H t and H2 r e c e p t o r s ( t a b l e I). M o r e o v e r , t h e y a r e active on c e r e b r a l H3 r e c e p t o r s in live rats a n d mice after o r a l a d m i n i s t r a t i o n doses in t h e m g . kg - t r a n g e . T h e y i n d u c e a d e c r e a s e in c e r e b r a l H A t u r n o v e r as m e a s u r e d b y a d e c r e a s e in [ 3 H ] H A synthesis f r o m e its [314] p r e c u r s o r o r in the H A c a t a b o l i t e l e v e l , t - m e thyl H A [4].
Tir6s ~ part : M. Garbarg_
THE H3 RECEPTOR
115
Table I. - - Potent and selective H3 receptor agonists.
Compound
(R) a- methylhistamine CH3
Relative potency (Histamine = 100) H3
H1
H2
1,500
0.5
1
1,800
0.03
0.2
6,200
< 0.1
0.6
I
lm-CH2- CH - NH2 (R) a, (S) 13- dimethylhistamine CH3CH3 I
I
Im-C.2-CH-CH-N--2 Imetit Im-CH2-CH2-S-C~ NH2 %NH
(i.a. =0_4)
For antagonists, thioperamide (Pr Robba) was selected [2] among a large series of derivatives. It is active at nanomolar concentrations and is very specific. Since oral administration of thioperamide to rodents elicits a strong elevation of cerebral HA turnover, it appears to be the first drug known to enhance the activity of cerebral histaminergic neurons. Thus, in the central nervous system, H 3 receptor ligands may have pQtential clinical uses for the two major functions of neuronal H A which are well established, i.e., control of arousal and control of appetite. Ha RECEPTORS IN THE AIRWAYS
The presence of H3 receptors in the lung was assessed by biochemical and functional studies. They control the biosynthesis of H A in the lung, a process which is likely to take place in mast cells, the key cells of allergic and inflammatory phenomena. When the endogenous pool of H A is label-
led by administration of the [ill]precursor, the H 3 receptor agonist (R)o~-methylHA inhibits the synthesis of H A in a dose-dependent manner, an effect reversed by the H3~antagonist thioperamide. Other inhibitory effects mediated by H3 receptors located on neurons of the respiratory tract have been shown in Pr Barnes laboratory (London, UK)[3]. (R)ot-methylHA modulates c h o l i nergic neurotransmission in the lung and inhibits the vagally-mediated contraction of isolated guinea-pig and human airways by stimulating H 3 receptors. Systemic administration of (R) amethylHA also strongly inhibits nonadrenergic noncholinergic (NANC) bronchoconstriction and neurogenic vascular leakage of airways mediated by the release of neuropeptides (substance P and calcitonin gene-related peptide). In contrast, the H 3 agonist has no effect on the bronchoconstriction and leakage induced by substance P, suggesting a presynaptic localisation of H 3 receptors on the peptidergic nerves in the airways. These various modulatory effects exerted by H 3 receptors in the lungs strongly suggest that I-I3 agonists may constitute a novel approach to the treatment of asthma by combining several beneficial effects.
BIBLIOGRAPHIE
1. ARRANGJM, GARBARGM, SCHWARTZJC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature, 302: 832-837, 1983. 2. ARRANG JM, GARBARG M, LANCELOT JC, LECOMTE JM, POLLARD H, ROBBA M, SCHUNACKW, SCHWARTZJC. Highly potent and selective ligands for histamine Ha-receptors. Nature, 327: 117-123, 1987. 3. BARNES PJ. Histamine receptors in the respiratory tract (pp 253-270). In : The histamine receptors_ Receptor biochemistry and methodology. JC SCHWARTZ,HL HAAS eds. Alan R. Liss, New York, 1991. 4 GARBARG M, TRUNG TUONG MD, GROS C, SCHWARTZ JC. Effects of histamine H~-receptor ligands on various biochemical radices of hlstaminergic neuron activity in rat brain. Eur J Pharrnacol, 164 : 1-11, 1989. 5. SCHWARTZJC, ARRANG JM, GARBARGM, POLLARD H, RUAT M. Histaminergic transmission in the mammalian brain. Physiol Rev, 71 : 1-52, 1991.
(~ Masson, Paris. Ann Fr Anesth Reanim, 12:114-115, 1993
The histamine Ha receptor: pharmacology and potential therapeutic applications Le troisi me r6cepteur de I'histamine" pharmacologie et applications th6rapeutiques potentielles M. GARBARG, J.C. SCHWARTZ Unit6 de Neurobiologie et Pharmacologie (U. 109) de I'INSERM, Centre PauI-Broca, 2 ter, rue d'Alesia, 75014 Paris
RI~SUM#: R6cemment, nous avons montr6 dans le cerveau l'existence d'un troisi~me r6cepteur de l'histamine (HA), dont la pharmacologie est clairement diff6rente de celledes r6cepteurs HI et H2- C'est un autor6cepteur port6 par le neurone histaminergique lui-m6me, qui r6gule la synth~se et la lib6ration de I'HA par un processus de r6troaction n6gative. Un puissant agoniste [(R)a-m6thylhistamine] et un puissant antagoniste (thiop6ramide) de ce r6cepteur ont 6t6 synth6tis6s. Ils ont une affinit6 n6gligeable pour les r6cepteurs H 1 et 1-12,Ces deux compos6s p6nbtrent dans le cerveau et peuvent modifier la vitesse de renouvellement de I'HA neuronale de faqon oppos6e. Comme I'HA est une amine d'6veil, l'antagoniste des r6cepteurs H3 pourrait augmenter la vigilance, alors que l'agoniste aurait des effets s6datifs. Les effecteurs des r6cepteurs H 3 sont aussi pr6sents sur des neurones non histaminergiques. Le r6cepteur H 3 exerce aussi des fonctions inhibitrices dans des tissus p6riph6riques. I1 a ainsl 6t6 mis en 6vldence dans l'appareil respiratoire ofi il inhibe la biosynth~se d'HA dans les mastocytes. De plus la (R)u-m6thylhistamine inhibe les contractions de la bronche humaine isol6e, prodmtes par stimulation 61ectrique du vague ainsi que la lib6ration des m6diateurs peptidergiques h partir des fibres C sensitives. L'identification du troisi~me r6cepteur de I'HA et des r6ponses mhibitrices vari6es, qu'induit sa stimulation dans divers organes, sugg~re des perspectives th6rapeutiques_
T h e actions o f h i s t a m i n e ( H A ) w e r e b e l i e v e d to b e m e d i a t e d b y o n l y two subclasses of r e c e p t o r s , H1 a n d H2, until t h e d i s c o v e r y of a t h i r d class o f H A r e c e p t o r s in t h e c e n t r a l n e r v o u s s y s t e m which differs f r o m t h e o t h e r t w o b y its p h a r m a c o l o g y . It has b e e n n a m e d H3 [5]. Initially, H 3 r e c e p t o r s w e r e i d e n t i f i e d as p r e s y n a p t i c a u t o r e c e p t o r s m o d u lating the synthesis a n d r e l e a s e o f H A via a n e g a tive f e e d b a c k p r o c e s s . H o w e v e r , e v i d e n c e has b e e n o b t a i n e d d r a w i n g t h a t H3 r e c e p t o r s a r e also l o c a t e d on n o n h i s t a m i n e r g i c n e u r o n s in t h e b r a i n as well as in p e r i p h e r a l tissues.
Ha RECEPTORS IN THE CENTRAL NERVOUS SYSTEM: DESIGN OF SELECTIVE AGONISTS AND ANTAGONISTS
In 1983, it was s h o w n that H A inhibits its o w n d e p o l a r i s a t i o n - i n d u c e d r e l e a s e via s t i m u l a t i o n o f
Presented at the meeting ~ New Trends in Anaphylactoid Risk in Anaesthesia ~. Nancy (France), 11-12 June 1992_
p r e s y n a p t i c r e c e p t o r s in b r a i n slices [1] H i g h l y p o t e n t a n d selective H 3 ligands w e r e d e v e l o p e d in c o l l a b o r a t i o n with t h e l a b o r a t o r i e s o f W . S c h u n a c k ( U n i v e r s i t y o f B e r l i n , G e r m a n y ) , M. R o b b a ( U n i versity of C a e n , F r a n c e ) a n d C . R . G a n e l l i n ( U n i versity C o l l e g e , L o n d o n , U K ) . T h e p r o t o t y p i c agonist is t h e chiral agonist ( R ) a - m e t h y l H A , after which (R)e~,(S)13-dimethylHA was d e v e l o p e d (pr Schunack). More recently, imetit (imidazolylethylis o t h i o u r e a ) was i d e n t i f i e d as a p o t e n t H 3 r e c e p t o r a g o n i s t (Pr G a n e l l i n ) . T h e s e t h r e e c o m p o u n d s a r e highly p o t e n t a n d selective, b e i n g a l m o s t d e v o i d of a n y action o n H t and H2 r e c e p t o r s ( t a b l e I). M o r e o v e r , t h e y a r e active on c e r e b r a l H3 r e c e p t o r s in live rats a n d mice after o r a l a d m i n i s t r a t i o n doses in t h e m g . kg - t r a n g e . T h e y i n d u c e a d e c r e a s e in c e r e b r a l H A t u r n o v e r as m e a s u r e d b y a d e c r e a s e in [ 3 H ] H A synthesis f r o m e its [314] p r e c u r s o r o r in the H A c a t a b o l i t e l e v e l , t - m e thyl H A [4].
Tir6s ~ part : M. Garbarg_
THE H3 RECEPTOR
115
Table I. - - Potent and selective H3 receptor agonists.
Compound
(R) a- methylhistamine CH3
Relative potency (Histamine = 100) H3
H1
H2
1,500
0.5
1
1,800
0.03
0.2
6,200
< 0.1
0.6
I
lm-CH2- CH - NH2 (R) a, (S) 13- dimethylhistamine CH3CH3 I
I
Im-C.2-CH-CH-N--2 Imetit Im-CH2-CH2-S-C~ NH2 %NH
(i.a. =0_4)
For antagonists, thioperamide (Pr Robba) was selected [2] among a large series of derivatives. It is active at nanomolar concentrations and is very specific. Since oral administration of thioperamide to rodents elicits a strong elevation of cerebral HA turnover, it appears to be the first drug known to enhance the activity of cerebral histaminergic neurons. Thus, in the central nervous system, H 3 receptor ligands may have pQtential clinical uses for the two major functions of neuronal H A which are well established, i.e., control of arousal and control of appetite. Ha RECEPTORS IN THE AIRWAYS
The presence of H3 receptors in the lung was assessed by biochemical and functional studies. They control the biosynthesis of H A in the lung, a process which is likely to take place in mast cells, the key cells of allergic and inflammatory phenomena. When the endogenous pool of H A is label-
led by administration of the [ill]precursor, the H 3 receptor agonist (R)o~-methylHA inhibits the synthesis of H A in a dose-dependent manner, an effect reversed by the H3~antagonist thioperamide. Other inhibitory effects mediated by H3 receptors located on neurons of the respiratory tract have been shown in Pr Barnes laboratory (London, UK)[3]. (R)ot-methylHA modulates c h o l i nergic neurotransmission in the lung and inhibits the vagally-mediated contraction of isolated guinea-pig and human airways by stimulating H 3 receptors. Systemic administration of (R) amethylHA also strongly inhibits nonadrenergic noncholinergic (NANC) bronchoconstriction and neurogenic vascular leakage of airways mediated by the release of neuropeptides (substance P and calcitonin gene-related peptide). In contrast, the H 3 agonist has no effect on the bronchoconstriction and leakage induced by substance P, suggesting a presynaptic localisation of H 3 receptors on the peptidergic nerves in the airways. These various modulatory effects exerted by H 3 receptors in the lungs strongly suggest that I-I3 agonists may constitute a novel approach to the treatment of asthma by combining several beneficial effects.
BIBLIOGRAPHIE
1. ARRANGJM, GARBARGM, SCHWARTZJC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature, 302: 832-837, 1983. 2. ARRANG JM, GARBARG M, LANCELOT JC, LECOMTE JM, POLLARD H, ROBBA M, SCHUNACKW, SCHWARTZJC. Highly potent and selective ligands for histamine Ha-receptors. Nature, 327: 117-123, 1987. 3. BARNES PJ. Histamine receptors in the respiratory tract (pp 253-270). In : The histamine receptors_ Receptor biochemistry and methodology. JC SCHWARTZ,HL HAAS eds. Alan R. Liss, New York, 1991. 4 GARBARG M, TRUNG TUONG MD, GROS C, SCHWARTZ JC. Effects of histamine H~-receptor ligands on various biochemical radices of hlstaminergic neuron activity in rat brain. Eur J Pharrnacol, 164 : 1-11, 1989. 5. SCHWARTZJC, ARRANG JM, GARBARGM, POLLARD H, RUAT M. Histaminergic transmission in the mammalian brain. Physiol Rev, 71 : 1-52, 1991.