LONG ACTING AGONISTS: A PHARMACOLOGICAL COMPARISON OF FORMOTEROL AND SALMETEROL

1
LONG ACTING ??-AGONISTSA PHARMACOLOGICAL
COMPARISON OF FORMOTEROL AND SALMETEROL
2
PRIMARY AMINO ACID SEQUENCE OF THE ?2-ADRENOCEPTOR
?2-agonist binding site
Extracellular surface
Cell membrane
Cytoplasmic surface
Transmembrane domain 1
Liggett and Green, 1997
3
CHEMICAL STRUCTURES
Salbutamol
Salmeterol
Fenoterol
For moterol
4
DURATION OF ACTION OF INHALED FORMOTEROL FIRST
ANECDOTAL IN VITRO INDICATION FOR LONG DURATION
OF ACTION
5
4
3

Asthma index

2



1
15
20
1
3
5
10
Time after aerosol administration (min)
Salbutamol
BD-40A (Formoterol)
Water
Ida et al., 1976
5
DURATION OF ACTION OF INHALED FORMOTEROL FIRST
PIVOTAL EXPERIMENT IN HUMANS
Oral route
Inhaled route
100
100
Salbutamol 4 mg
80
80
Formoterol 6 µg
60
60
capacity ()
Salbutamol 100 µg
40
40
20
20
Formoterol 80 µg
0
0
-20
-20
420
480
420
480
0
60
120
180
240
300
360
0
60
120
180
240
300
360
Time (min)
Time (min)
6
IN VITRO MODEL PREDICTING LONG DURATION
150
100
Response to acetylcholine ()
50
0
p
0
10
20
30
40
50
Time (min)
Terbutaline
Formoterol

Control
Salmeterol
Jeppsson et al., 1994
100 mmol/l
10 mmol/l
1000 mmol/l
7
POTENCIES OFFORMOTEROL AND SALMETEROL
100
Relaxation ()
50
0
-10
-9
-8
-7
-6
-5
Log (mol l-1)
Salmeterol
Formoterol
Terbutaline
Källström et al., 1992
8
INTRINSIC ACTIVITIES OFFORMOTEROL AND SALMETEROL
100
Relaxation ()
50
0
-10
-9
-8
-7
-6
-5
Log (mol l-1)
Salmeterol
Formoterol
Terbutaline
..
..
Kallstrom et al., 1992
9
DURATION OF ACTION IN CONSCIOUS GUINEA PIGS
100
80
60
Inhibition of histamine- induced
bronchoconstriction
40
20
0
-20
0
30
60
90
120
180
300
360
240
Time (min)
Formoterol
Salbutamol
Salmeterol
Nials et al., 1994
0.12 mM
0.2 mM
0.01 mM
10
ONSET AND DURATION OF ACTION DEMONSTRATED BY USE
OF TRACHEAL STRIPS
2
7 hours
0
Salmeterol (10 nM)
Propranolol (100 nM)
2
Electrically-stimulated force of contraction (g)
0
Salbutamol (30 nM)
2
0
Formoterol (0.3 nM)
Nials et al., 1994
11
THE EXOSITE BINDING HYPOTHESIS
HO-CH2
HO
OH
-
CH
-
CH2
-
NH
-
CH2
-
CH2
-
-
-
-
O
CH2
CH2
CH2
CH2
?-adrenoceptor
exosite
Green et al., 1996
12
THE PLASMALEMMA MICROKINETIC DIFFUSION THEORY

• The lipophilicity of any molecule is determined
  by its chemical structure
• The lipophilicity of a ?2-agonist determines how
  the molecule partitions between the aqueous phase
  and the cell membrane
• This process contributes to how a ?2-agonist
  approaches the receptor, its speed of onset and
  duration of action

13
THE PLASMALEMMA MICROKINETIC DIFFUSION THEORY
Aqueous biophase
Cell membrane with ?2-receptor
Salbutamol Hydrophilic Short duration Fast onset
Formoterol Intermediate Long duration Fast onset
Salmeterol Lipophilic Long duration Slow onset
Anderson et al., 1993
14
?2-AGONIST AFFINITIES AND SELECTIVITIES FOR ?1-
AND ?2-ADRENOCEPTORS
pK I
Competing Agonist
Selectivity ? 2 / ? 1
? 2 Site
? 1 Site
Isoproterenol
6.10 0.10
6.28 0.09
1
Salmeterol
5.69 0.05
7.97 0.06
190
Formoterol
6.32 0.04
8.10 0.05
60
Fenoterol
5.67 0.05
6.33 0.07
5
Soterenol
6.13 0.13
6.06 0.04
1
Salbutamol
4.71 0.16
5.83 0.06
13
Values are mean SEM of all experiments yielding
affinity values (pK I ) for ? 1- and ?
2-adrenoceptors Selectivity is the ratio of the
inhibition constants 10 ( pKI ? 2 - pK I ? 1 )
Roux et al., 1996
15
?2-AGONIST INTERACTIONS SALMETEROL INHIBITS
FORMOTEROL-INDUCED RELAXATION
100
Relaxation ()
50
0
-9
-8
-7
-6
-5
Formoterol (Log mol/l)
Formoterol 10 mmol/l salmeterol
Formoterol alone
Relaxant effect of 10 mmol/l salmeterol
Jeppsson et al., 1992
16
CONCLUSION

• Formoterol and salmeterol are long-acting
  ?2-agonists with substantial pharmacological
  differences.
• The differences comprise
• chemical structure
• potency
• mode of action at the ?2-receptor
• selectivity
• efficacy (i.e. full/partial agonism)