Page 1 of 24
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`AstraZeneca Exhibit 2015
`Lannett v. AstraZeneca
`IPR2015-01629
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`Current Medicinal Chemistry
`
`i
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`Editor:
`.
`_
`p‘ Atta-ur-Rahman (HEJ Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan)
`Co-Editors:
`
`.
`
`David J. Craik (Centre for Drug Design and Development University of Queensland, St. Lucia, QLD 4072, Australia) ’
`Scott L. Dax (The R.W. Johnson Pharm. Res. Inst., Welsh and McKean Roads, Spring House, PA 190477-0776, USA)
`David C. Rees (Pharma Division, AKZO, Organon Laboratories Ltd., Newhouse, Lanarkshire, ML1 SSH, Scotland, UK)
`Associate Editors:
`Koichi Shudo (University of Tokyo, Tokyo, Japan)
`Donald T. Witiak (Univ. Wisconsin-Madison, Madison, USA)
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`Bruce L. Currie (Midwestern University, Chicago, USA)
`Francis Johnson (State Univ. of New York, New York, USA)
`‘V ‘Alan P. Kozikowski (Georgetown, Univ., Washington, USA)
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`Paul D. Leeson (Merck, Sharp & Dhome, Harlow, UK)
`J.-F. Liégeois (Universite de Liége, Liege, Belgium)
`Ai Jeng Lin (Walter Reed Inst., Washington, USA)
`John A. Lowe III (Pfizer, Groton, USA)
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`Kenji Mori (Science University of Tokyo, Tokyo, Japan)
`C.G. Newton (Rhone-Poulenc, Dagenham, UK)
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`

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`Current Medicinal Chemistry
`
`Volume 4, Number 6, December,‘ 1997
`
`contents
`
`Rational Development of‘ New Sleeping _
`Sickness Drugs
`.
`Serge Van Calenbergh and Pier Herdewijn
`
`Migraine: Current Drug Discovery Trend
`Charles Q. Meng -
`'
`
`Interaction of the Antitumor Antibiotic
`Streptonigrin with Metal Ionsand DNA
`Margaret M. Harding and Georgma V. Long
`
`Peptidic and Non-peptidic Neurotensin Analogs
`dette Cusack,p Abdul Fauq and
`’
`
`421
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`This is to acknowledge that_
`supplied by Dr. B.K. Trivedl,
`Ann Arbor, MI 48105, USA.
`the CCK—B receptor bas
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`Aims and Scope
`
`Current Medicinal Chemistry aims to cover all the
`latest and outstanding developments in medicinal
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`Page 4 of 24
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`
`Migraine: CurrentDrug Discovery Trend1
`
`Current Medicinal Chemistry, 1997, 4, 385-404
`
`Charles Q. Meng2
`
`AI/e/ix Biopharmaceuticals lnc., 6850 Goreway Drive, Mississauga, Ontario, Canada
`L4V 1V7
`'
`
`Abstract: Migraine is a common disorder severely affecting normal life.
`There is no perfect treatment for it
`to date. Sumatriptan is the first,
`antimigraine drug developed through contemporary medicinal chemistryf
`, Since sumatriptan binds with high affinity to 5—HT1Da, 5—HT1 Db and 5-HT1F =
`receptors it has been proposed that one or more of these receptor subtypes is involved in the
`pathophysiology of migraine. It is almost certain that the 5—HT1DB receptor causes the cardiac
`adverse reactions of sumatriptan.
`»
`
`Several compounds are currently under clinical development or about to reach the market for the
`treatment of migraine. However, most of them are structurally similar to sumatriptan, bind to the 5-
`HT1D[3'receptor and therefore have potential cardiac adverse reactions. An obvious advantage of
`someof the compounds over sumatriptan is the higher oral bioavailability than sumatriptan.
`Some penetrate the CNS whereas sumatriptan does not.
`It remains to be seen whether CNS
`penetration is beneficial.
`
`Vascular and neurogenic mechanisms have been proposed for migraine. Both theories are
`backed up by scientific data and countered by controversies.
`
`Selective ligands at the respective 5-HT1Do,, 5—HT1D[, and 5—HT1; receptors will possibly provide ’
`not only scientific tools for migraine research but also satisfactory antimigraine drugs.
`
`Introduction
`
`Migraine [1] is an episodic headache syndrome of
`recurrent attacks. The characteristic symptom is
`throbbing and intense one-sided headache, often
`accompanied by nausea, vomiting and sensitivity to
`light and sound. There may be prodromal symptoms
`such as mood change or altered behavior several hours
`before the attack. About 15% of migraine sufferers
`experience an aura up to an hour before the onset of
`the headache. Migraine with an aura is called classic
`migraine and migraine without an aura is called common
`migraine. The recurrent attack may vary widely in
`intensity, frequency and duration, with each attack
`lasting 4-72 hours.
`'
`
`Migraine is estimated to affect about 8% of the adult
`population [2]. However, the real figure can be much
`higher since most people with migraine are never
`diagnosed by a physician or treated with prescription
`
`This article is dedicated to my mentors (in chronological order). Prof.
`Weixin Chen, Prof. Manfred Hesse, Dr. Werner Hofheinz, Prof. Stephen
`Hanessian, and Dr. Suman Rakhit.
`‘
`‘
`
`2Current address: AtheroGenics,
`Norcross, Georgia 30071, USA
`
`lnc., 3065 Northwoods Circle,
`
`medications [3]. The prevalence of migraine is higher in
`younger individuals (12-38 years of age) and in
`individuals with lower socioeconomic status. And it is s
`
`more common in women than in men, with 17.6% of
`women and 6.0% of men in the United States suffering
`severe migraine presently. There has ‘been an
`interesting epidemiological study of a monastery on a
`peninsula where no woman is allowed to set foot and
`the monks fast for six months per year, avoid milk and
`fats, and have religious services from 2 a.m. until 8 a.m.
`The migraine prevalence amounted to a mere 1.7% [4].
`This maymean that celibacy and lack of sleep or food V
`are not risk factors of migraine [5]. The cause of
`migraine is unknown. The attack may be precipitated by
`air pollution, perfumes, hypoglycemia, oversleeping,
`fatigue or certain drugs.
`in "some individuals even
`chocolate, cheese, alcohol or monosodium glutamate
`can provoke an attack of migraine.
`
`Although migraine has been known since ancient
`times as a common, highly distressing disorder causing
`severe disruption of normal daily life, there is not yet a
`satisfactory treatment today [3, 6]. Simple analgesics
`such as acetylsalicylic acid and paracetamol are widely
`used to treat migraine. They are often effective for mild
`or moderate attacks, but inadequate for severe attacks.
`
`0929-8673/97 $8.00+.00
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`©1997 Bentham Science Publishers B.V.
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`.
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`Page 5 of 24
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`

`
`385 Currant Medicinal Chemistry, 1997, Vol. 4, No. 6
`
`Charfes Q. Meng
`
`The efficacy of an oral dose of these drugs is often
`restricted because absorption is limited by gastric stasis
`that can occur during a migraine attack. Co-
`administration of antlemetics is required. The efficacy of
`acetylsalicylic acid in migraine is possibly due to its anti-
`inflammatory action, perhaps through direct effect on
`intracranial arteries [7]. Nonsteroidal anti-inflammatory
`, drugs such as naproxen and ibuprofen are popular for
`the treatment of acute migraine attacks. However,
`these drugs are often only moderately effective and
`cause gastrointestinal side effects [6].
`
`Ergotamine and dihydroergotamine have long been
`used for the treatment of migraine. Clinical studies
`showed that oral or parenteral ergotamine produces a
`degree of symptom relief in migraine [8]. However, an
`analysis of placebo-controlled studies with ergotamine
`in the acute treatment of migraine showed little_
`evidence that ergotamine has superior efficacy over
`placebo [9]. A number of side effects associated with
`ergotamine have been reported in the literature [10,
`C 11], including myocardial infarction, ischemia of limb
`extremities and fibrotic changes. Long—term use has
`led to reported cases
`of« ergotamine-induced
`headache, vascular activity and subclinical ergotism.
`Ergotamine is an alpha-adrenergic antagonist and
`seretonergic agonist. It has vaso— and venoconstricting
`actions.
`Compared
`with
`ergotamine,
`' dihydroergotamine is a weaker arterial vasoconstrictor
`and more potent and selective venoconstrictor.
`it has
`lower incidence of side effects than ergotamine [3].
`
`,
`
`' Prophylactically migraine is treated with a diverse
`range of drugs. Beta-blockers such as propranolol and
`metoprolol are widely used. Studies have shown that
`they are more effective than placebo in reducing attack
`frequency [12, 13]. The side-effects of these drugs are
`nausea, fatigue,
`insomnia, diarrhea and dizziness.
`Certain calcium channel blockers are used in migraine
`prophylaxis. Flunarizine reduces the frequency of
`migraine" attacks in about 50% of patients [14-16].
`However, some drugs of this class are not active in
`migraine prophylaxis or may even worsen the condition
`[6]. Methysergide, a 5-HT2 antagonist, reduces the
`frequency of migraine attacks by about 50% in 25-50%
`of patients. The side-effects include nausea, vomiting,
`abdominal discomfort, dizziness and drowsiness [6].
`The herb feverfew, Tanacerum parthen/‘um, has
`prophylactic properties with respect to the frequency
`and severity -of migraine attacks. The active principle is
`believed] to be the sesquiterpene parthenolide. The
`mechanism of action is proposed to be the
`demonstrated inhibition of platelet aggregation by
`feverfew extract
`[17,
`18]. Acetylsalicylic acid,
`fluoxetine, cyproheptadine, phenelzine and sodium
`valproate are also used for migraine prophylaxis [3, 6].
`
`Serotonin Receptors
`
`Serotonin (5—hydroxytryptamine; 5-HT; 1) isa
`biogenic amine neurotransmitter
`in the nervous
`system, which is also present in high concentration in
`blood platelets and the enterochromaffin cells of
`gastrointestinal mucosa [19]. 5-HT has long been
`implicated in the pathophysiology of migraine [20-23].
`The evidences are: a) platelet levels of 5-HT fell by up .
`to 45% at the onset of a migraine attack [24]; b) an
`increase in the urinary excretion of the main metabolite,
`5-hydroxyindole acetic acid has been observed "[20];
`and c) administering 5-HT itself intravenously would
`alleviate migraine attacks [25, 26].
`
`
`
`5-HT causes multiple effects in the central nervous,
`gastroenteric and cardiovascular systems. These
`effects are mediated via a variety of membrane bound
`receptors on smooth muscles and neurons. To date
`seven different classes of 5-HT receptors have been
`described [27-30]: 5-HT1, 5—HT2, 5-HT3, 5-HT4, 5—HT5,
`5-HT5 and 5-HT7. With the exception of the 5-HT;; class
`all other classes have been shown to be members of
`
`the G-protein coupled receptor’ super family [29].
`Within many of the seven classes there are multiple
`subtypes. The 5-HT1 class contains five subtypes so
`far: 5-HT-IA, 5-HT1Da, 5-HT1D[3, 5-HT1E and 5'HT1F. The
`5-HT1B receptor found in rodents is the species analog
`of the human 5—HT1DB receptor. Recently Hardig et al.
`[31] recommended that the 5—HT1D0, receptor subtype
`be renamed the 5-HT“; and the 5-HTH35 receptor
`subtype renamed h 5—HT1B. This new nomenclature is
`constructive and should be adopted for
`future
`publications.
`In fact it has been used in some recent
`publications [32-34]. However, for a review article like
`this which deals with previous publications, it is more
`appropriate to use the conventional nomenclature.
`In
`
`most previous publications the term 5-HT“; is not clear.
`it means in most cases both 5-HT1D(, and 5-HT]DB.
`
`Sumatriptan, a new treatment for acute migraine with
`demonstrated efficacy, binds with high affinity to
`cloned human 5-HT1D,,, 5-HTH35 and 5-HT“: receptors
`expressed in cell
`lines [35, 36],
`implicating these
`
`
`
`
`
`Page 6 of 24
`
`

`
`Current Discovery .
`
`receptors as possible targets for migraine therapy. The
`search for antimigraine drugs has been focused on
`these subtypes of receptors since the discovery of
`sumatriptan.
`
`receptor
`The 5-HT1Da and 5—HT1D[; (5-HT1B)
`subtypes have been shown to be present in a variety of
`species including human [35, 37, 38], rabbit [39], rat
`[40, 41], mouse [42], dog [43-45] and guinea pig [34].
`Species differences
`of
`these
`receptors
`in
`pharmacology can be widely divergent. The deduced
`amino acid sequences of the rabbit 5-HT1D0, and 5-
`HTH35 receptors show 91-92% identity with their
`respective human homologs. The pharmacological
`profile at the rabbit receptors is generally consistent
`with that of the human receptors. However, sumatriptan
`displayed a 65-fold lower affinity than 5-HT at the rabbit
`5—HT1D;3 receptor, but only 4-fold lower than 5-HT at the
`human 5—HT1D[3 receptor
`[39]. Methiothepin, a
`nonselective 5—HT1/2 receptor antagonist, binds almost
`equally at the human 5-HT1D(, and 5-HT1D,3 receptors
`but displays 16-fold 5-HT1D[5/5-HT1D,, selectivity at the
`rabbit receptors [46]. The rodent 5-HT1B receptor
`shares a high degree of amino acid sequence identity
`With the human 5-HT1D[3 receptor [35, 40, 41, 47], but
`has, a distinct pharmacology. Adrenergic antagonists
`such as pindolol display high affinity for the cloned rat
`5-HT1B receptor [41] but show at least 100—fold lower
`affinitytfor its species analog, the recombinant human
`5-HT1D[3 receptor [35]. The molecular basis for this
`difference has been localized to a threonine residue in
`TM7 of the human 5-HT1D[5 receptor. Mutation of this
`residue to asparagine confers a 5-HT1B pharmacology
`with high affinity for pindolol [48]. The rabbit 5-HT1D5
`receptor also contains a threonine at this position and
`has low affinity for pindolol [39]. Furthermore, although
`. ketanserin exhibits 70-fold 5-HT1D0, over 5-HT1'D[5
`binding selectivity at the human [49] and analogous rat
`receptors [50] and a 20-fold selectivity at the rabbit
`receptors [46], it does not discriminate between these
`receptors in the dog [45].-Therefore, although the 5-
`HTH30, and 5-HT1D[3 receptors possess structural
`similarities across species, marked species differences
`in pharmacological profiles exist and can complicate the
`interpretation of data regarding the functional activation 1
`of
`those receptors across multiple species.
`It
`IS.-
`important
`to
`identify a
`species where
`the
`pharmacological profile of the 5—HT1D0, and 5-HT1D[3
`receptors closely resemble that at their human analogs.
`
`_
`
`5-HT1-like is an ambiguous term. It was often used
`before individual 5-HT receptor subtypes were cloned.
`The 5-HT1-like can be clearly distinguished from some
`5-HT receptors such as 5—HT1A. However, it is not easy
`to distinguish them from 5-HT“; receptors. Studies
`have shown that both 5-HT1D0, and 5—HT1D,3 receptors
`resemble the 5-HT1-like receptors. Depending on
`’ tissue localization, 5-HT1—like receptors can be 5—HT1D0,
`
`Current Medicinal Chemistry, 1997, Vol. 4. No-T 6 387
`
`[receptor or 5-HT1DBreceptor or both of them. it is not
`clear if the 5-HT”: receptor is also involved. Kaumann
`and coworkers foundthat ketanserin which would
`occupy 5—HT1D0, receptor failed to block 5-HT induced
`contraction of isolated human coronary arteries and
`therefore concluded that the 5—HT1DB receptor is more
`likely the candidate for the 5-HT1-like receptor of
`human coronary arteries [51]. There is molecular
`evidence that the 5-HT1D5 receptor is abundant in
`[ human coronary arteries [52].
`it has been shown that
`the 5-HT1'D[; receptor, but not the 5-HT1D,, receptor, is
`present in human and bovine cerebral arteries [53].
`Recently a rabbit saphenous vein 5- HT1-like receptor
`gene was cloned.
`its amino acid sequence and
`receptor binding profile classified it as a 5—HT1D,3
`receptor [54]. The existing evidence also indicates that
`the 5-HT1-like receptor in the dog saphenous vein is a
`5-HT1DB receptor though certain anomalies leave room
`for skepticism [45]. The wholegissue can only be
`resolved when selective agonists and antagonists at
`these receptor sites are available.
`
`The human 5-HT”: receptor‘ was cloned in 1993
`[36]. Sumatriptan and several ergot alkaloids have a
`high affinity for it, suggesting a possible role for the 5-
`HT“: receptor in migraine [55].]
`A
`
`Migraine Mechanisms
`
`the
`regarding
`theories
`two
`are
`There
`the vascular and
`pathophysiology of migraine,
`neurogenic mechanisms. The vascular mechanism was
`first proposed by Graham and Wolff in 1938 [56]. Ray
`and Wolff [57] demonstrated that the throbbing pain of
`migraine could be replicated by faradic or mechanical
`stimulation of dural arteries or the Circle of Willis but not
`of other tissues.’ The vascular mechanism suggests
`that migraine headache results from an excessive
`dilation of extracerebral cranial (mainly scalp and dural)
`arteries and arteriovenous anastomoses [58]. Friberg
`et al. have detected middle cerebral artery dilation in
`migraine [59]. Visser et al. have found a large
`arteriovenous malformation in a migraineur and,
`selective embolization to reduce the blood.supply
`resulted in resolution of the headache [60]. The
`vasodilatation of migraine is suggested to be caused by
`lower endogenous 5-HT activity at the initiation of
`migraine. Cephalovascular pharmacological studies
`have revealed that 5-HT constricts large extracerebral
`arteries and arteriovenous anastomoses while dilating
`arterioles [61].
`
`Alcohol and vasoconstrictor drugs such as ergot
`alkaloids are instrumental in ending migraine episodes
`[62]. Humphrey et al. have found that sumatriptan
`mimics the effect of 5-HT as a powerful vasoconstrictor
`in dog and primate basilar arteries [63, 64]. Further
`
`Page 7 of 24
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`

`
`388 CurrentMedicinaIChemistry, 1997, Vol. 4, No.6
`
`studies on isolated human dura mater showed that
`
`both 5-HT and sumatriptan produce similar degrees of
`vasoconstriction when injected into the perfusion
`saline at low concentrations [65]. Friberg et al. [59]
`have found that during a migraine attack the middle
`cerebral artery blood velocity on the headache-affected
`side of the head was significantly lower than the
`unaffected side. After treatment with sumatriptan and
`subsequent amelioration the velocity turned to normal.
`The change in velocity suggests that the cranial artery
`was distended and that sumatriptan causes constriction
`of the artery in vivo and thereby amelioration of the
`migraine.
`
`Sumatriptan has no antinociceptive effects even
`after iv. administration [58, 63, 66]. This strongly
`supports the vascular mechanism of migraine.
`Excessive dilation on the extracerebral cranial
`vasculature is an essential factor, though perhaps not
`the only one,
`in the development of the headache
`phase of migraine -[58]. However, while the vascular
`mechanism for migraine has gained wide acceptance,
`there is not total agreement as to its validity. Normal
`vasodilatation alone is not enough to cause pain. The
`vascular mechanism can not explain the hemicrania and
`the unilateral supersensitivity to pain in migraine.
`
`Heyck proposed in 1969 that the vasodilatation of
`migraine primarily‘ involves cranial arteriovenous
`anastomoses, but not arterioles [67]. This explains the
`facial pallor associated with migraine. Drugs that
`decrease arteriovenous shunting could be effective for
`migraine. According to this hypothesis Saxena and
`coworkers have developed an animal model
`for
`migraine by’ measuring arteriovenous anastomotic and
`tissue fractions of carotid blood flow in different animal
`
`including the cat [68-70], dog [71] and pig
`species,
`[70, 72-74]. The pig seems to be an especially suited
`species, particularly because of the impression that the
`pharmacological
`response of skiniblood vessels
`resembles that in human. A number of antimigraine
`drugs including sumatriptan were found to constrict
`cranial arteriovenous anastomoses in such a model
`[75].
`
`Set against the vascular mechanism pf migraine is
`the neurogenic mechanism first put
`forward by
`Moskowitz in 1979 and backed up by elegant
`experimentation [76—83]. This mechanism has received
`
`major exposure. According to Moskowitz, currently
`unknown triggers stimulate the trigeminal ganglion
`which innervate vasculature within the cephalic tissue,
`the so-called trigeminovascular system. Then the
`‘axons on the vasculature release vasoactive
`neuropeptides including substance P, calcitonin gene-
`related peptide, and neurokinin A which are potent
`vasodilators [84]. These released neuropeptides then
`initiate a series of events leading to neurogenic
`
`Charfes Q. Meng
`
`inflammation (vasodilatation and plasma extravasation),
`a consequence of which is pain. This neurogenic
`inflammation can be blocked by ergot alkaloids and
`sumatriptan at a dose similar to that required to treat
`acutemigraine headaches [77, 78, 80-83, 85, 86].
`Sumatriptan also blocks
`chemically induced
`trigeminovascular activity [80, 81] and neurogenically
`mediated dural plasma extravasation [77, 78].
`
`Nicotine has been identified as a stimulant of
`
`perivascular sensory nerves in guinea-pig isolated
`basilar artery, producing NK1
`receptor-mediated
`relaxation [87]. Nicotine—induced relaxation is inhibited ‘
`by sumatriptan and UK—14, 304 (an (12 agonist),
`suggesting that inhibitory prejuctional 5—HT1 receptors
`and ot2—adrenoceptors occur on the sensory nerve
`terminals in this cranial blood vessel.
`In this study
`O’Shaughnessy and Connor showed the first in vitro
`evidence for an inhibitory effect of sumatriptan on
`sensory neurotransmission. It is possible that such an
`~ action in man could contribute towards the ability of
`sumatriptan to alleviate migraine headache. However,
`the relative importance of such a neuronal action and
`the ability of such an effect to lead to antimigraine
`activity will only be established by the future clinical
`evaluation of compounds active at
`the neuronal
`receptor but lacking vasoconstrictor activity. Selective
`5-HT1D receptor agonists will most probably fall into this
`class." Therefore, the mode of action of sumatriptan is
`not necessarily vasoconstriction. It must at least include
`a neuronal component. .
`
`Just which of the two mechanisms is right is still a
`debate [88]. One thing in common is that both
`mechanisms act in the periphery. This is consistent with
`the fact that under normal circumstances sumatriptan
`cannot penetrate the blood—brain barrier in substantial
`amounts [89]. Given some other drugs with similar
`pharmacological actions that are also useful in migraine,
`such as dihydroergotamine, have access to the central
`nervous system binding sites [90] the prospect of
`central locus of action of antimigraine drugs would then
`stand as a third alternative to explain the action.
`Experimental data have demonstrated that sumatriptan
`can interact with the transmission of nociceptive input
`in central trigeminal neurones suggesting inhibitory
`modulation of synapses at the second order neurone if
`entry of the drug into the CNS has been facilitated [83].
`It is unknown whether the integrity of the blood—brain
`barrier is impaired during migraine attacks.
`
`On the molecular level both proposed mechanisms
`rely on 5-HT receptors, the vascular mechanism.
`involving 5-HT receptors in cranial blood vessels while
`the neurogenic mechanism involving 5-HT receptors in
`the trigeminal ganglion. This is again a very complicated
`issue. To date the major research tool
`in this area is
`sumatriptan. However, sumatriptan has high affinity for
`
`Page 8 of 24
`
`

`
`Current Discovery
`
`currenruedicinarchemisn-y, 1997, Vol. 4. No.6 389
`
`5-HT1Da, 5-HT1DB and 5—H1”1F receptors as shown in
`‘Table 1. Several other recently described compounds
`of this class now in clinical trials for migraine have a very
`similar 5-HT receptor profile. Which of these three
`receptors is important for the antimigraine efficacy in
`man is not entirely clear to date.
`
`_Recently, Hamel and coworkers examined the
`expression of mRNA transcripts for
`the_
`three
`sumatriptan—sensitive 5-HT receptors in human
`
`trigeminal ganglia and cerebral blood vessels [91]. The
`results indicate that all three receptors are expressed in
`human trigeminal ganglia while only 5—HT1DB and 5-
`HT1F receptors are clearly present in cerebral blood
`-vessels. The mRNA transcripts for the 5—HT1Dl3
`subtype, but not the 5-HT1Da subtype, are present in
`human and bovine blood vessels [53]. Based on these
`data Hamel concluded that the 5-HT1DBgreceptor
`mediates the sumatriptan-induced vasoconstriction in
`human brain vessels. This conclusion is also supported
`
`Table 1. Binding Affinities of Some 5-HT1 Receptor Ligands (Ki, nM)
`
`1.1
`s—
`
`35, 36, 42
`
`36, 49 -
`190
`
`181
`
`35
`
`41, 46
`
`'
`
`1
`
`36, 49, 42
`
`A'“ld‘*a“
`CGS-1206B
`CF’ 122,288
`5-CT
`
`Dihydroergotamine
`
`N, N—Dipropy|-5-CT
`
`GR 127935
`5-HT
`
`8-Hydroxy-2- dipropy|amino)tetra|in
`Ketanserin 1
`
`L—694,247
`LY-334370
`
`Metergoline
`
`Methiothepin ’
`5—Methoxytryptamine
`
`1
`
`Methysergide
`a-Methy|—5HT
`2-Methyl-5-HT
`
`5-Methyltryptamine
`
`1-(1-Naphthyl)piperazine
`
`Naratriptan
`
`Oxymetazoline
`RAPP
`
`1 Ftauwolscine
`Flitanserin
`
`Ftizatriptan
`
`Sumatriptan
`»
`,
`.1-(3-Trifluorom9lhY"Ph9“Y')P'P9'aZ'”9
`Tryptamine
`Yohimbine
`
`Zolmitriptan
`
`_
`*
`.
`1
`3.4
`.
`“
`‘
`«
`35, 41
`_ Hm-
`35. 36
`35
`521
`2409
`.
`
`35, 36, 42
`
`Page 9 of 24
`
`

`
`
`
`390 Current Medicinal CI_1emish'y,. 1997, Vol.4, No. 6
`
`Charfes 0. Meng
`
`‘sheets
`
`‘
`
`""1?ati—»...:u.--..fi€G,§‘
`3-53%,:
`
`
`
`
`
`.,,;m=“>w',,v
`
`
`
`
`
`3,4,4:,~.,.4-,r¢__;~r=:v:4:mm»-
`
`by the finding that the mRNA expression for the 5-
`HT1DB, but not the 5—HT_1D‘0, receptor was‘ detected in
`peripheral blood vessel in several species including
`humans [92]. .Hamel and coworkers ,s___t:udied_ the
`pharmacological profile of the 5-HT receptor which
`induces contraction of bovine isolated cerebral arteries.
`Several 5-HT receptor agonists were tested for the
`ability to inducegvasoconstriction. The potencies were
`compared with those obtained for
`the same
`compounds at
`the cloned 5'—HT1DO, and 5—HT1D[;
`receptors. Only the correlation with the 5-HT1iDB
`subtype reached —a statistically significant
`level,
`suggesting that the "receptor involved may correspond
`to a 5—HT1’DB subtype [93]. There is also evidence for
`the presence of presynaptic 5—HT1D5
`receptor
`messenger RNA in neurons of the rat trigeminal ganglia
`[94].
`
`- Hamel’s data provided une