Effects of the
`Blocking and Cardiovasucular
` Adrenoceptor
`a Combined
`s
`of Amosulalol
`(YM-09538),
`Optical Isomers
`and 18-Adrenoceptor Blocking Agent, and the Corresponding
`
`Desoxy Derivative
`(YM-11133) in Rats
`
`INAGAKI, Masayuki
` Kazuo HONDA, Chieko NAKAGAWA, Osamu
`
`Toichi TAKENAKA
`and Masaaki TAKEDA
`
`SHIBASAKI,
`
`Department of Pharmacology, Central Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd.,
` 1-1 -8 Azusawa, Itabashi-ku, Tokyo 174, Japan
`
`
`
`Accepted April 23, 1986
`
`(YM
`of amosulalol
`activities of the enantiomers
`pharmacological
`Abstract-The
`09538),
`a combined
`a
`and 8-adrenoceptor
`antagonist,
`and
`the corresponding
`desoxy derivative
`(YM-1 1133) were
`investigated
`in the cardiovascular
`system of
`rats. The optical
`isomers of amosulalol and YM-1 1133 antagonized
`the vasopressor
`effect of phenylephrine
`and
`the positive
`chronotropic
`effect of
`isoproterenol
`in
`normotensive
`pithed rats. Based on DR2 values
`(,ag/kg,
`i.v.) obtained
`from Schild
`plots,
`(+)-amosulalol
`and YM-11133
`(DR2=30) were approximately
`10
`times
`more potent
`than
`(-)-amosulalol
`(DR2=324)
`in blocking
`a,-adrenoceptors.
`For
`(3, -adrenoceptors,
`in contrast,
`(-)-amosulalol
`(DR2=107)
`was
`approximately
`60 times more potent
`than
`(+)-amosulalol
`(DR2=6460), which was almost equi
`potent with YM-1 1133 (DR2=3250).
`The results
`indicate
`that the optical
`isomers
`of amosulalol
`interact differently with a,
`and i3, -adrenoceptors.
`The effects of
`these phenethylamines
`on blood pressure and heart rate were studied
`in urethane
`anesthetized
`rats (i.v.). The rank order of hypotensive
`potency
`in anesthetized
`rats
`((+)-=desoxy>(-)-form)
`was consistent with the rank order of a,-adrenoceptor
`rats.
`antagonism
`in pithed
`In contrast,
`(-)-amosulalol
`having a more potent'
`adrenoceptor
`antagonist
`activity than (+)-amosulalol
`and YM-11133 only produced
`dose-dependent
`bradycardia
`at the hypotensive
`doses.
`The results
`indicate
`that
`a,
`the vascular
`and cardiac
`(3, -adrenoceptor
`blocking
`activities of the optical
`isomers of amosulalol
`contribute
`to their hypotensive
`and bradycardia,
`respectively.
`Thus, the racemate of amosulalol
`appears
`to exert an overall activity reflecting
`the
`activities of the individual
`isomers.
`
`sulfamoyl
`a
`(YM-09538),
` Amosulalol
`is a newly
`derivative,
`phenethanolamine
`agent
`with
`developed
`anti hypertensive
`combined
`and E3-adrenoceptor
`blocking
`a
`activities
`(1, 2). In conscious
`spontaneously
`hypertensive
`rats (SHR),
`renal hypertensive
`rats and DOCA/salt
`hypertensive
`rats,
`single oral administration
`of amosulalol
`(3
`30 mg/kg)
`lowered
`acutely
`systolic
`blood
`pressure with a duration of over 6 hr. Repeated
`oral administration
`of amosulalol
`50 mg/kg,
`b.i.d.,
`for 12 weeks produced
`not only an
`antihypertensive
`effect without
`evidence
`of
`
`a
`
`in plasma
`reductions
`also
`but
`tolerance,
`and heart
`rate
`in SHR with
`renin activity
`established
`hypertension
`(3). In adrenoceptor
`blocking studies
`in isolated
`tissues of rats and
`guinea pigs (2, 4) and in radioligand binding
`studies
`(5),
`amosulalol
`displayed
`a
`two
`orders of magnitude
`greater
`selective
`an
`tagonism
`of
`a, -adrenoceptors
`than
`a2
`adrenoceptors
`but amosulalol
`showed
`no
`selectivity
`towards
`31 or (32-adrenoceptors.
`In guinea
`pig vascular
`tissues,
`amosulalol
`blocked
`the actions
`of norepinephrine
`and
`isoproterenol
`at pre
`and
`post-junctional
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
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`
`

`
`normotensive
`in pithed
`activities
`blocking
`by antagonizing
`the a1
`rats were assessed
`adrenoceptor
`mediated
`pressor
`effect
`of
`phenylephrine
`and
`the
`(31 -adrenoceptor
`mediated
`positive
`chronotropic
`effect
`of
`isoproterenol,
`respectively.
`Cardiovascular
`functions
`were
`investigated
`in urethane
`anesthetized
`rats (i.v.).
` Adrenoceptor
`blocking activity: Wistar rats
`were anesthetized with ether and pithed by
`inserting
`a steel
`rod (1.5 mm
`in diameter)
`through
`the orbit
`and
`foremen magnum
`down
`into the spinal canal. Immediately
`after
`pithing, the animals were ventilated artificially
`with room air in a tidal volume of 1 ml/100 g
`body weight at a rate of 50 breaths/min
`using
`a
`rodent
`respirator
`(SN-480-7,
`Shinano.
`Tokyo,
`Japan). After bilateral vagotomy
`at
`the
`neck
`level,
`systemic
`arterial
`blood
`pressure was measured
`at
`the
`left carotid
`artery via a pressure
`transducer
`(MPU-0.5,
`Nihon Kohden, Tokyo, Japan)
`and recorded
`on a Nihon Kohden
`recorder
`(RJG-3004).
`Heart
`rate was measured with
`a cardio
`tachometer
`(RT-5, Nihon Kohden)
`triggered
`by pulse
`pressure.
`In
`the
`first
`series
`of
`experiments,
`the postsynaptic
`vascular
`a1
`adrenoceptor
`antagonist
`activity was studied
`after a 15 min period when
`cardiovascular
`parameters were allowed
`to stabilize. Phenyle
`phrine was
`injected
`into
`the
`right femoral
`vein
`through
`a cannula
`at intervals of ap
`proximately
`5 to 10 min until an increase
`in
`diastolic blood pressure of 80 to 120 mmHg.
`The dose-response
`curves
`for phenylephrine
`were constructed
`before and 15 min after i.v.
`treatment with
`each dose
`of antagonists.
`Three dose
`levels of antagonists
`given at an
`interval of approximately
`1 hr were examined
`in the same animal.
`In a second
`series of
`experiments,
`the
`cardiac
`(31 -adrenoceptor
`antagonist
`activity was
`investigated
`in the
`other pithed
`rats. Dose-response
`curves
`for
`isoproterenol which was injected at an interval
`of approximately
`5 to 1 5 min until an increase
`in heart
`rate of 80 to 100 beats/min were
`obtained
`before and 15 min after
`i.v. treat
`ment with each dose of antagonists,
`and then
`three
`dose
`levels
`of
`antagonists
`were
`examined
`in the same animal as described
`above. The doses of antagonists were given
`at an
`interval of approximately
`90 min.
`In
`
`(YM
`of amosulalol
`structure
`Fig. 1. Chemical
`09538)
`and
`the corresponding
`desoxy derivative
`(YM-11133).
`The asterisk denotes
`the point of
`asymmetry.
`
`in the mem
`changing
`membranes without
`brane properties of the smooth muscle cells.
`The inhibitory
`effects of amosulalol may be
`due to inhibition of a1 and (3-adrenoceptors.
`High concentrations
`of amosulalol
`had only
`weak
`inhibitory actions on a2-adrenoceptors
`located
`in perivascular
`adrenergic
`nerve
`endings
`and
`in the
`smooth muscle mem
`brane of the mesenteric vein (6). Amosulalol
`has one asymmetric
`center at the
`l3-carbon
`(Fig. 1), so two enantiomers
`of this com
`pound
`can exist.
`a
`and
`l3-Adrenoceptor
`subtype
`blocking
`activities
`of
`the optical
`isomers of amosulalol
`and the corresponding
`desoxy
`derivative
`(YM-11133)
`have been
`investigated
`in
`anesthetized
`rats
`(7),
`preliminarily,
`and
`in
`isolated
`tissues
`(8).
`(+)-Amosulalol
`and YM-11133 were one log
`unit order more potent and
`less potent
`than
`(-)-amosulalol
`in blocking
`a,
`and
`,31
`adrenoceptors,
`respectively,
`in both
`the
`anesthetized
`rat and the isolated
`tissue.
`a1
`
` In this paper, postsynaptic
`vascular
`adrenoceptor
`and cardiac
`t31-adrenoceptor
`antagonist
`activities
`and
`cardiovascular
`effects of the enantiomers
`of amosulalol
`and
`YM-11133 were
`investigated
`in rats in vivo.
`
`Materials and Methods
`
` Male normotensive Wistar
`rats (Shizuoka
`Agriculture Coop. Assoc., Shizuoka,
`Japan)
`weighing 280-330 g were used for evaluating
`the postsynaptic
`vascular a1 and cardiac 131
`adrenoceptor
`antagonist
`activities
`and
`cardiovascular
`functions.
`The postsynaptic
`vascular
`a1
`and
`cardiac
`,31 -adrenoceptor
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1040-2
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`
`

`
`and E3, -adrenoceptor
`the study on both a,
`antagonist
`activities, both phenylephrine
`and
`isoproterenol
`administered
`in saline-treated
`rats
`(control
`study)
`repeatedly
`gave
`in 4
`trials
`dose-response
`curves whose
`ED50
`values were not significantly
`different
`from
`each other
`(data
`not shown).
`The ED50
`values, doses of phenylephrine
`required
`to
`elicit a 50 mmHg
`increase
`in diastolic blood
`pressure and those of isoproterenol
`required
`to elicit a 50 beats/min
`increase
`in heart rate,
`were calculated
`from
`the log dose-response
`curves,
`and
`then
`the
`dose-ratio
`was
`calculated
`(3). The adrenoceptor
`antagonist
`activities were quantified
`by the method of
`Arunlakshana
`and Schild
`(9). The dose of
`antagonist
`required
`to produce
`an agonist
`dose-ratio
`of 2 (DR2) and the slope of the
`regression
`line were calculated.
` Study
`in anesthetized
`rats: Rats were
`anesthetized with urethane
`(1.2 g/kg,
`s.c.),
`and
`the vagal nerves were bilaterally cut at
`the neck level. The tracheas were cannulated
`to facilitate breathing,
`but the animals were
`permitted
`to respire spontaneously.
`Systemic
`arterial blood pressure
`and heart
`rate were
`measured
`as described
`above. Mean arterial
`pressure was calculated
`as the diastolic blood
`pressure plus one-third of the pulse pressure
`(mmHg). The test drugs were non-cumula
`tively
`injected
`into
`the
`right
`femoral vein
`through
`a cannula at an
`interval of 20 min
`and in a volume of 1 ml/kg.
`(YM
` Drugs: Amosulalol
`hydrochloride
`the cor
`09538),
`its optical
`isomers
`and
`responding
`desoxy
`derivative
`(YM-11133)
`were
`prepared
`by Dr. Fujikura
`in
`the
`Chemistry Department
`of Yamanouchi
`Phar
`maceutical
`Co. The optical
`isomers were
`resolved
`into (-) and (+)
`tartaric acid salts
`of the enantiomers which were
`recrystallized
`to constant
`rotation
`in order to determine
`the
`absolute configuration
`and subsequently
`con
`verted
`to
`hydrochloride
`salts.
`Physico
`chemical
`properties
`of
`the optical
`isomers
`were as follows
`m.p. 158-160,
` R (-)-Amosulalol:
`
` [a]20 -30.4
`(c=1, MeOH)
` S-(+)-Amosulalol:
`m.p. 158-160,
`
` [a]20 +30.7
`(c=1, MeOH)
`(-)-Phenylephrine
`hydrochloride
`and
`(-)
`isoproterenol
`hydrochloride
`(Tokyo Kasei,
`
`methanesul
`phentolamine
`Japan),
`Tokyo,
`Japan),
`pro
`(Ciba-Geigy, Takarazuka,
`fonate
`pranolol hydrochloride
`(Sigma Chemical Co.,
`U.S.A.) were obtained commercially. Prazosin
`hydrochloride
`(Pfizer
`Inc., U.S.A.) was
`kindly donated
`by
`its manufacture.
`The
`enantiomers
`and racemate of amosulalol
`and
`the other drugs were dissolved
`in physio
`logical
`saline
`(0.9 % w/v)
`but YM-11133
`and prazosin were dissolved
`in a few drops
`of 1 N HCI and distilled water,
`and
`then
`saline or 0.5% methylcellulose
`solution was
`added
`to them up to the appropriate volume.
`Ascorbic
`acid
`(0.01%,
`Takeda
`Chemical
`Industry,
`Japan) was added
`to the
`isopro
`terenol-containing
`solution
`to
`retard
`oxidation. Doses are expressed
`in terms of
`the salts, except
`for YM-11133, which was
`expressed
`as the base.
`text are
`in the
` Data analysis: All results
`expressed
`as the mean±S.E.M.
`or the mean
`and 95% confidence
`limits with the number of
`experiments.
`Comparisons
`of values before
`and after
`the drug
`in the same group of
`pithed and anesthetized
`rats, and those of the
`vehicle and drug-treated
`group
`in conscious
`SHR were made by Student's
`paired and non
`paired
`t-test,
`respectively.
`P values
`less than
`0.05
`are
`considered
`to
`be
`significant.
`Regression equations were calculated
`by the
`method of least squares.
`
`Results
`
`blocking effects
`Adrenoceptor
`and
`pressure
` The basal diastolic
`blood
`heart
`rate were 55±2 mmHg and 305±5
`beats/min
`(n=32),
`respectively,
`in pithed
`rats. ED50 values for phenylephrine
`and iso
`proterenol,
`doses of phenylephrine
`required
`to elicit a 50 mmHg increase
`in diastolic blood
`pressure and those of isoproterenol
`required
`to elicit a 50 beats/min
`increase
`in heart rate,
`were
`2.7±0.2
`/cg/kg
`and 9.2±0.4
`ng/kg
`(n=16),
`respectively,
`before
`treatment with
`antagonist.
`(+)-,
`(-)
`and
`(±)-Amosulalol
`did not significantly
`(P>0.05)
`decrease basal
`blood pressure and heart rate.
` Postsynaptic
`vascular
`a, -adrenoceptor
`antagonistic
`activity: The log dose-response
`curves with respect
`to the increase
`in diastolic
`pressure
`elicited
`by phenylephrine,
`before
`and after pretreatment with
`(±)-amosulalol
`
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`
`

`
`(-)
`i.v.),
`/cg/kg,
`and 1000
`300
`(100,
`(300, 1000 and 3000 gig/kg, i.v.),
`amosulalol
`(+)-amosulalol
`and YM-11133
`(30, 100,
`300 and 1000 /tg/kg,
`i.v.) are shown
`in Fig.
`2. (+)-,
`(-)
`and (+)-Amosulalol
`and YM
`1 1133 caused a parallel shift of the log dose
`response
`curves
`for phenylephrine
`to
`the
`right. Based on DR2 values
`(Table 1), (+)
`amosulalol
`and YM-11133 were 10.7 and
`10.9 times more potent
`than
`(-)-amosulalol
`
`vaso
`phenylephrine-induced
`in antagonizing
`pressor
`response,
`respectively.
`I n the same
`experimental
`condition,
`prazosin
`and phen
`tolamine,
`a-adrenoceptor
`antagonists,
`also
`antagonized
`the
`phenylephrine-induced
`vasopressor
`effects with DR2 values of 1.66
`(n=12)
`and
`128
`(n=16)
`jig/kg,
`i.v.,
`respectively,
`whereas
`propranolol
`hardly
`affected
`the
`log dose-response
`curves
`for
`phenylephrine
`up to 1 mg/kg,
`i.v. Both (+)
`
`derivative (YM-1 1133)
`and the corresponding
`(+)-amosulalol
`(-)-and
`Fig. 2. Antagonism by (±)-,
`effects
`(Left panel) and
`isoproterenol-induced
`tachycardiac
`of phenylephrine-induced
`vasopressor
`effects (Right panel) in pithed rats. The results are the mean±S.E.M. of 4 animals.
`
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`
`

`
`Table 1. Alpha-1 and beta-1 adrenoceptor blocking activities of amosulalol,
`responding desoxy derivative (YM-111 33) in pithed rats
`
`its optical isomers and the cor
`
`vasopressor effect . U : Antagonism of isoproterenol-induced
`a : Antagonism of phenylephrine-induced
`tachy
`cardiac effect. C : DR2 values (,ug/kg, i.v.) and slope of the Schild plot are the mean with 95% confidence
`limits in parentheses.
`n : Number of experiments.
`
`amosulalol and YM-1 1133 were 18 times less
`but 4 times more potent than prazosin and
`phentolamine,
`respectively,
`in
`blocking
`vascular a1 -adrenoceptors;
`however,
`(-)
`amosulalol was a weaker antagonist for a,
`adrenoceptors.
`antagonistic
` Cardiac
`P, -adrenoceptor
`activity: Figure 2 also illustrates the log dose
`response curves for isoproterenol, before and
`after pretreatment with
`(-)
`and
`(+)
`amosulalol (100, 300, 1000 and 3000 ,ug/kg,
`i.v.),
`(+)-amosulalol
`(3000,
`10000
`and
`30000
`/ug/kg, i.v.) and YM-11133
`(1000,
`3000 and 10000
`,ug/kg,
`i.v.). (-)
`and
`(±)-Amosulalol dose-dependently produced
`a parallel shift of the log dose-response
`to
`isoproterenol to the right, but (+)-amosulalol
`and YM-11133 did not significantly cause a
`parallel shift to the right except the highest
`dose of 10000 pig/kg. Based on DR2 values
`(Table 1), (-)-amosulalol,
`in contrast to its
`ai -adrenoceptors, was 60.4 and 30.4 times
`more potent than (+)-amosulalol
`and YM
`11133,
`respectively,
`in antagonizing
`iso
`proterenol-induced
`positive
`chronotropic
`response.
`Propranolol,
`a
`/3-adrenoceptor
`antagonist, also antagonized
`isoproterenol
`induced positive chronotropic effects with
`a DR2 value of 28.2 pg/kg,
`i.v. (n=12),
`whereas prazosin did not cause any changes
`in the response to isoproterenol up to 1 mg/
`kg, i.v. (+)-Amosulalol,
`(-)-amosulalol
`and
`YM-11133 were 182, 3.8 and 94 times less
`
`(+)-amosulalol
`and
`(-)
`Fig. 3. Effects of (t)-,
`(YM-11133)
`on
`derivative
`and
`the corresponding
`mean blood pressure
`(MBP) and heart rate (HR) in
`urethane-anesthetized
`rats. The
`results
`are
`the
`mean±S F M of 6-R animals
`
`propranolol
`than
`respectively
`potent,
`/31-adrenoceptors.
`antagonizing
`cardiac
`rats
`Study in anesthetized
`and heart
` Resting mean arterial pressure
`rate of urethane-anesthetized
`rats were 114
`±4 mmHg
`and 459±9
`beats/min
`(n=28),
`
`in
`
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`
`

`
`and (±)-Amosulalol
`respectively. (+)-, (-)
`and YM-11133
`(0.001-0.3 mg/kg,
`i.v.)
`dose-dependently
`decreased mean arterial
`pressure. The reductions
`in mean arterial
`pressure elicited by (-)
`and (±)-amosulalol
`were associated with bradycardia, whereas
`(+)-amosulalol
`and YM-11133 did not sig
`nificantly affect heart rate (Fig. 3). The ED20
`values (i.e., dose required to reduce mean
`arterial pressure by 20%) for (+)-,
`(-)-,
`(±)-amosulalol
`and YM-11133 were 2.6,
`47.3, 7.9 and 21.0 /cg/kg, i.v., respectively.
`Based on ED20 values, (+)-amosulalol was
`18 times more potent in hypotensive activity
`than (-)-amosulalol.
`Prazosin also lowered
`mean arterial pressure with an ED20 value of
`2.5 gig/kg, i.v. (n=6), but it did not affect
`heart rate. In contrast, propranolol did not
`significantly (P>0.05)
`reduce blood pressure,
`but dose-dependently
`lowered heart rate.
`(-)
`and (+)-Amosulalol dose-dependently
`reduced heart rate, whereas
`(+)-amosulalol
`and YM-11133 hardly influenced heart rate
`at their hypotensive doses (Fig. 3).
`
`Discussion
`
`the
`its optical
`isomers and
` Amosulalol,
`corresponding desoxy derivative (YM-1 1133)
`have been evaluated for their adrenoceptor
`blocking activities
`in vivo. Normotensive
`pithed rats were used for estimating an
`tagonistic properties of (±)-, (-)
`and (+)
`amosulalol and YM-1 1133 at the a, and /,
`adrenoceptor
`subtypes.
`These
`phene
`thanolamines dose-dependently
`antagonized
`the a, -adrenoceptor-mediated
`vasopressor
`response
`to phenylephrine
`and
`the
`/3,
`adrenoceptor-mediated
`positive chronotropic
`response to isoproterenol
`in pithed rats. In
`this
`experimental
`procedure,
`prazosin
`exerted a dose-dependent
`shift to the right
`of the dose-response
`curves for phenyle
`phrine with a DR2 value of 1.66 /cg/kg, IN.,
`without affecting the dose-response curves
`for isoproterenol,
`in contrast to propranolol
`which did not affect the a, -adrenoceptor
`mediated vasopressor responses but caused
`dose-dependent
`inhibition
`of
`the
`/3,
`adrenoceptor mediated positive chronotropic
`effects with a DR2 value of 28.2 /cg/kg, i.v.
`Based on DR2 values, (+)-amosulalol was
`found to be 11 times more potent than (-)
`
`in blocking vascular a, -adre
`amosulalol
`noceptors. The a, -adrenoceptor
`blocking
`activity of YM-11133 was almost equipotent
`with
`(+)
`but not
`(-)-amosulalol.
`This
`result in pithed rats is consistent with that of
`our previous studies in anesthetized rats (7)
`and in the isolated rabbit aorta (8). (+)
`Amosulalol was,
`in contrast
`to
`its a,
`adrenoceptor blocking activity, 60 times less
`potent
`than
`(-)-amosulalol
`in blocking
`cardiac
`,3, -adrenoceptors.
`The
`/3, -adre
`noceptor blocking activity of YM-11133 was
`less potent than that of (-)-amosulalol,
`but
`nearly equipotent with that of (+)-amosulalol,
`similar to the findings for the blockade of
`a, -adrenoceptors. This result with respect to
`(3, -adrenoceptor blocking potency
`in this
`pithed rat is consistent with
`that of our
`previous reports (7, 8). These results indicate
`that stereochemical requirements of a,
`and
`j31 -adrenoceptors
`differ
`for
`the
`optical
`isomers
`of
`amosulalol, with
`the
`a,
`adrenoceptor
`subtype
`favoring
`the
`(+)
`isomer and the desoxy form and the
`/3,
`adrenoceptor favoring the (-)-isomer.
` The
`rank order of potency
`for
`adrenoceptors
`in this study ((-)->desoxy
`=(+)-forms of amosulalol)
`is in agreement
`with
`the order predicted by the Easson
`Stedman hypothesis, a theory governing the
`adrenoceptor mediated activity of the optically
`active phenethanolamines
`possessing
`an
`asymmetric
`/3-carbon
`atom
`(10-12).
`In
`contrast,
`the potency order for a, -adre
`noceptor,
`in this study ((+)=desoxy>(-))
`the
`is different
`from
`that predicted by
`Easson-Stedman
`hypothesis. Phenethanol
`amines have been previously studied on
`activation of a and (3-adrenoceptors and on
`blockade of /3-adrenoceptors
`(10, 12), but
`not
`on
`blockade
`of
`a-adrenoceptors.
`Stereoselectivity
`in a-adrenoceptor
`blocking
`agents has been a relatively limited area of
`research due
`to
`the
`fact
`that most a
`adrenoceptor antagonists do not possess the
`phenethylamine. Recent
`studies
`on
`the
`stereoisomers
`of
`labetalol
`(13)
`and
`medroxalol
`(14), which
`also
`display
`combined a
`and (3-adrenoceptor blocking
`activities, have indicated that the a and /3
`adrenoceptor
`blocking properties are not
`distributed uniformly among
`the
`individual
`
`(3,
`
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`Exhibit 1040-6
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`
`

`
`isomers. The results of the present study are
`consistent with those reported for labetalol
`and medroxalol. However, the studies of the
`stereochemical
`requirements for blockade of
`adrenoceptors by labetalol and medroxalol
`are complicated by the fact that both of these
`compounds possess two asymmetric centers,
`resulting in four possible isomers. In contrast
`to
`labetalol
`and medroxalol,
`amosulalol
`possesses only one asymmetric center and
`then
`just
`two
`isomers exist.
`It appears,
`therefore that amosulalol, its enantiomers and
`the corresponding
`desoxy derivative are
`useful pharmacological
`tools for studying
`stereochemical
`requirements for a
`and a
`adrenoceptor
`antagonists
`of
`the phene
`thanolamine class (8).
`hypotensive
`the
`
` In anesthetized
`rats,
`potency order was: prazosin=(+)-amosulalol
`>YM-11133>
`(-) -amosulalol >>propranolol.
`Based on ED2O values, (+)-amosulalol was
`18 times more potent in hypotensive activity
`than (-)-amosulalol.
`This isomeric activity
`ratio was consistent with that of a vascular
`a1 -adrenoceptor,
`but not consistent with
`that of cardiac 81-adrenoceptor antagonism.
`(-)
`and (±)-Amosulalol produced brady
`cardic activity, but (+)-amosulalol and YM
`11133 did not at the hypotensive dose
`range. This result may be caused by the
`cardiac al -adrenoceptor blocking property.
` The adrenoceptor blocking effects of (±)
`amosulalol was approximately half that of
`(+)-amosulalol
`for vascular a, -adrenoceptors
`and half that of (-)-amosulalol
`for cardiac
`Q1-adrenoceptors.
`The
`hypotensive
`and
`bradycardic effects of (±)-amosulalol were
`intermediate between those of (+) and (-)
`amosulalol
`in anesthetized
`rats (i.v.). Thus,
`(±)-amosulalol
`is a racemic mixture with
`equal proportions of the two enantiomers,
`and as such, the overall activity may be due
`to the sum of the activities of the individual
`enantiomers.
`
`References
`
`
` 1 Takenaka, T., Shiono, K., Honda, K., Asano, M.,
` Miyazaki, I. and Maeno, H.: Antihypertensive and
` adrenoceptor blocking properties of new sul
` fonamide-substituted phenylethylamines. Clin.
` Exp. Hypertens. [A] 4, 125-137 (1982)
` 2 Takenaka, T., Asano, M., Berdeaux, A. and
`
`blocking hemo
` Giudicelli, J.-F.: Adrenoceptor
`a
` dynamic and coronary effects of YM-09538,
` new combined a and (3-adrenoceptor blocking
` drug,
`in anesthetized
`dogs. Eur. J. Pharmacol.
` 85, 35-50
`(1982)
` 3 Honda, K., Takenaka, T., Shiono, K., Miyata
` Osawa, A. and Nakagawa, C.: Autonomic and
` antihypertensive
`activity of oral amosulalol (YM
` 09538),
`a combined
`a
`and
`(3-adrenoceptor
` blocking agent
`in conscious
`rats. Japan.
`J.
` Pharmacol. 38, 31-41
`(1985)
` 4 Tomioka, K., Yamada, T. and Takenaka, T.:
` Comparison of airway obstraction
`induced by
` propranolol and YM-09538
`(a combined a and
` (3-adrenoceptor blocking drug). Arch. Int. Phar
` macodyn. Ther. 256, 97-107
`(1982)
` 5 Asano, M., Hashimoto, H. and Nakashima, M.:
` Affinities for a and /3-adrenoceptor
`subtype of
` YM-09538,
`a new combined
`a
`and ~-adre
` noceptor
`antagonist,
`by
`radioligand
`binding
` assay. Arch. Int. Pharmacodyn. Ther. 262, 34-46
`
` (1983)
`6 Fujioka, M. and Suzuki, H.: Effects of amosulalol
` on the electrical responses of guinea-pig vascular
` smooth muscle
`to adrenoceptor
`activation. Br.
` J. Pharmacol. 84, 489-497
`(1985)
` 7 Takenaka, T., Honda, K., Fujikura, T., Niigata, K.,
` Tachikawa, S. and Inukai, N.: New sulfamoyl
` phenethylamines,
`potent
`a,-adrenoceptor
` antagonist.
`J. Pharm. Pharmacol. 36, 539-542
` (1984)
` 8 Honda, K., Takenaka, T., Miyata-Osawa, A. and
` Terai, M.: Adrenoceptor
`blocking properties of
` the stereoisomers
`of amosulalol
`(YM-09538)
` and the corresponding
`desoxy derivative
`(YM
` 11133).
`J. Pharmacol. Exp. Ther. 236, 776-783
` (1986)
`and Schild, H.O.: Some
`0.
` 9 Arunlakshana,
`uses of drug antagonists.
`Br. J.
` quantitative
` Pharmacol. 14, 48-58
`(1959)
`10 Easson, L.H. and Stedman, E.: Studies on the
`
` relationship
`between
`chemical
`consistent
`and
` physiological action. V. Molecular dissymmetry
` and physiological activity. Biochem. J. 27, 1257
` 1266 (1933)
`11 Patil, P.N., Patel, D.G. and Krell, R.D.: Steric
` aspects of adrenergic drugs. XV. Use of isomeric
` activity
`ratio
`as a criterion
`to differentiate
` adrenergic
`receptors.
`J. Pharmacol. Exp. Ther.
` 176, 622-633
`(1971)
`12 Patil, P.N., Miller, D.D. and Trendelenburg, U.:
` Molecular geometry and adrenergic drug activity.
` Pharmacol. Rev. 26, 323-392
`(1974)
`13 Brittain, R.T., Drew, G.M. and Levy, G.P.: The a
` and
`(3-adrenoceptor
`blocking
`potencies
`of
`
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`IPR2016-00379
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`

`
`in
`stereoisomers
`individual
`its
`and
` labetalol
`
`in isolated
`tissues. Br. J.
`dogs
` anaesthetized
` Pharmacol. 77, 105-114
`(1982)
`14 Cheng, H.C., Revis, O.K., Jr., Grisar, J.M.,
`
`Claxton, G.P., Weiner, D.L. and Woodward,
`J.K.: Antihypertensive
`and adrenergic
`receptor
`blocking
`properties
`of
`the
`enantiomers
`of
`medroxalol. Life Sci. 27, 2529-2534
`(1980)
`
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