Neuroscwnce& BiobehavtoralRevwws. Vol 16. pp 75-82 o Pergamon Press plc. 1992 Pnnted m the U S A

0149-7634/92 $5130 + 00

Centrally Active 5-HT Receptor Agonists and Antagonists D E R E K N. M I D D L E M I S S A N D M A R K D. T R I C K L E B A N K

Merck Sharp and Dohme Research Laboratories, Neurosctence Research Centre Terhngs Park, Eastwwk Road, Harlow, Essex, CM20 2QR UK

MIDDLEMISS, D N AND M D TRICKLEBANK Centrally acnve 5-HT receptor agontsts and antagomsts NEUROSCI BIOBEHAV REV 16(1) 75-82, 1992 --Eleven subtypes of central 5-HT receptor have so far been postulated, four of which have been cloned (5-HTIA, 5-HTIc, 5-HTIo and 5-HT2) and a fifth (the 5-HT s receptor) purified The present review discusses the agomsts and antagonists which act at these subtypes w~th respect to their degree of selectwlty and in vlvo potency Selecnve agonlsts exist for the 5-HT)A, 5-HT~B and 5-HT 3 receptors and selectwe antagomsts for the 5-HT_, and 5-HT3 receptors. 5-HTIA, 5-HTtB, 5-HT~c, 5-HT)D, 5-HT:, 5-HT 3 receptors

Agomsts

Antagomsts

other receptor subtypes remain to be identified (Fig 1 and Tables 1-6) The purpose of the present review is to summanse the drugs which interact with the 5-HT receptor subtypes and to attempt to define the affinity, selectwlty and in VlVO potency at central 5-HT receptors of the tools which are currently being used to define the functional correlates of these receptors. It is hoped that this knowledge wtll enable a critical view to be estabhshed towards the interpretatton of in vitro and in VlVO studtes of the actions of these drugs in the CNS. For the purpose of this review a detailed analysis of drugs acting at 5-HT.~ receptors has not been attempted since to date no information has been reported as to their in VlVO CNS potency

IN 1986 Bradley et al. (7) reviewed the actions of 5-hydroxytryptamlne (5-HT, serotonin) at both central and peripheral receptor sites and concluded that the actions of 5-HT could be explained on the basis of an interaction at three mare classes of receptor These included an heterogeneous group, but with common high affinity for 5-HT, designated 5-HT~-like. and two other major populations, 5-HT, and 5-HT 3 Since 1986 there has been considerable interest in the development of drugs which selectively interact wtth each class of receptor which has resulted m a multldisclphnary approach to the validation of the Bradley et al. classification As a consequence, there are now some indications that 5-HT2 (49,51) and 5-HT 3 (66) receptors are also heterogeneous and a further class, denoted 5-HT 4, has been postulated (24). At the time of writing the proposition that there are multiple subtypes of 5-HT2 and 5-HT 3 receptors is still premature and this review has, therefore, assumed these groupings to be homogeneous. In Fig. 1 the characteristics of the receptors which have gamed the most attention are displayed Four of the 5-HT receptor subtypes (5-HT~A. 5-HT~c 5-HT2 and 5-HT~D) have been cloned (8.32) and the Ion channel assocmted with the 5-HT 3 receptor has been purified (52,53). Each is differentially located in discrete regions of the central nervous system (CNS) and the effector system which subserves the actions at these receptors has been defined. Thus, the 5-HT~A (21), 5-HT m (6), 5-HT~D (40) and 5-HT4 (24) receptors are linked to the adenylate cyclase second messenger system, the 5-HT~c (15) and 5-HT2 (16) receptors are coupled to the productton of phosphot~dylinosltol and the 5-HT3 receptor mediates fast depolanslng responses by opening monovalent cation selective membrane channels (5). Progress in defining receptor selective 5-HT agonlsts and antagomsts with actions m the CNS has been somewhat slower than the biochemical studies outlined above Some success has been achieved m the case of 5-HT~A receptor agomsts and 5-HT2 and 5-HT 3 receptor antagontsts, but selectwe compounds at the

5-HT~ARECEPTOR AGONISTS AND ANTAGONISTS The 5-HTtA receptor was first postulated as a result of studies of the blphaslc displacement of the radloligand [3H]5-HT by the neuroleptlc, spiperone (63). The discovery was quickly followed by the identification of a selective 5-HTiAreceptor agontst, (8-OH-DPAT, Table 1). This compound shows very high affinity and selectivity for the 5-HT~A receptor In vitro (56) and is a potent agonlst m VlVO (Table I). A number of other 5-HTIA receptor agonlsts have been identified with high affintty (e g , MDL 72832, Table 1), but 8-OH-DPAT remains the most commonly used tool for the defimtton of 5-HTiA-mediated responses The discovery of 5-HT~A receptor antagonists remains problematic Initial studies identified a number of [3-adrenoceptor antagonists with antagonist actions at the 5-HT~A receptor These include cyanopmdolol, plndolol and propranolol. Despite the fact that all of these compounds are nonselecttve with respect to [3-adrenoceptors and indeed to the 5-HTIB receptor (Table 1), they have been extremely useful in defining the functional consequences of 5-HT~,,, receptor activation, particularly when they are used m conjunction with a selective 5-HTjA receptor agomst such as 8-OH-DPAT (74). Other antagonists which are also

75

76

MIDDLEMISS AND TRICKLEBANK

CENTRAL5-HT RECEPTORS

Subtype

5"HTIA

Clones Amino Aclds Molecular Welghl

Locahon (examples)

5"HTI B

5"NTI C

5"HTI D

5"HT2

Human

Rat

Human

Rat

421

460

44KD

52KD

5-HT 3

449 250KD

Hlppocampus

Substantla

Chorold

Substanha

Raph~

Nlgra

Plexus

Nlgra

Cortex Olfactory System

Caudate

Caudate

Claustrum

Globus pallldus

Globus pallldus

Cortex

5-HTa

NTS Cortex

Superior Collicull

Effector

cAMPST

cAMP,I.

PIT

cAMP,I.

PI'I"

Ion channel

cAMPt

Agonlsts

8-OH-DPAT Ipsap)rone Buspltone"

CP-93129 RU 24969" CGS 12066B° MCPP*

MCPP° TFMPP* RU 24969*

5-CT* Sumatrlptan"

DOI DaB DaM

M-chlorophenylblguanlde

Metaclopramide* BRL 24924"

Antagonlsts

*Not selective

Metitepln* 13-Adtenoceptor antagonists* Mesulerglne* Spiperone* Ritanserin * MDL 73005 NAN- 190"

Metergollne'?

Ketonserin ICl 169369 Sergolexole

MDL 72222 ICS 205-930 Ondansetron Granlsetron

ICS 205-930*

NTS. Nucleus tractus solltarlus

FIG 1 Summary of the properhes of subtypes of the 5-HT receptors For details of drug names see Tables 1--6

nonselective, but for h~storlcal reasons are important 5-HTIA receptor tools, are metltepm [the prototyplcal 5-HT~-hke receptor antagonist (7)] and splperone, the latter drug being the first compound shown to discriminate 5-HT~A from 5-HT m receptors (63) Two more recent antagonists which may prove valuable m defining 5-HT~A receptors are NAN-190 and MDL 73005. Whdst these drugs are the most potent antagonists of the 5-HT~A receptor described to date, both are partial agomsts at 5-HT~A receptors and NAN-190 additionally suffers from a lack of specificity with resect to cq-adrenoceptors (Table 1). 5-HT~a RECEPTORAGON1STSAND ANTAGONISTS The 5-HT~B receptor was originally defined as the low-affinity component of 5-HT~ receptor binding, that is, that part of the binding which was only weakly displaced by splperone (63). Subsequent studies identified a third site, the 5-HT~c receptor (61), which was also present m rodent brain, but the 5-HT~a receptor binding site can be separately identified by the judicious use of 5-HT~c blocking drugs such as mesulergme or mlanserm or by the use of the radloligand [~-'Sl]iodocyanopmdolol (37). After the discovery of the 5-HT~a binding site in 1981, progress m identifying potent agonlsts and antagonists was relauvely rapid until about 1985 when It was realised that the 5-HT~B receptor was specific to the rat, mouse and opossum and, in partlcular, was absent from the human brain (39). Interest in the identification of specific hgands for this site and the definition of functional correlates of actwatlon of the receptor have, as a result, been muted (57,73). Nevertheless, a number of relatively powerful, but nonspeClfiC, 5-HT m receptor agomsts have been identified (Table 2)

and their effects assessed both m vitro and in vwo The pyridinyl mdole, RU 24969, has received the most attention because of the initial, but unverified claim, that it was selective for the 5-HTm receptor [(69), see also Table 2]. The rational design of an analogue of RU 24969, CP-93,129, may serve to redress the balance since the compound displays both high affinity and selectivity for the 5-HT~B receptor (54) and may provide a much needed impetus for research into the functional role of the 5-HTm receptor. Research into this receptor subtype would also be facilitated by the availability of selective 5-HT~a receptor antagonists (Table 2) A number of 13-adrenoceptor antagonists possess antagorest activity at the 5-HTjB receptor, but all are more potent at the [3-adrenoceptor itself and most possess significant affinity for the 5-HTIA receptor. The only other useful 5-HT m receptor antagomst is metltepm, but the lack of selectivity of this drug makes it a difficult tool to use in functional studies. 5-HT~c RECEPTORAGONISTSAND ANTAGONISTS The 5-HT~c receptor is pnnclpally concentrated in the charold plexus of mammahan brain, but is also found in cortical reglans (61,62) and has, thus, received considerable attention since its identification in 1985. To date, however, only three moderately potent, directly acting 5-HTlc receptor agonlsts have been identified: MCPP, TFMPP and MK-212 (Table 3). Unfortunately, none is particularly selective with respect to other 5-HT receptors. A similar problem with respect to poor selectivity is found with 5-HT~c receptor antagonists. Thus, the most potent drugs at the 5-HT~c receptor, mesulergine and dtansenn, possess con-

5-HT R E C E P T O R A G O N I S T S A N D A N T A G O N I S T S

77

TABLE 1 5-HTIA RECEPTOR AGONISTS AND ANTAGONISTS

5-HTLA pKr,

Other Activity pKD

Dose Range In Vtvo (mg/kg)

References

Agonlsts MDL 72832 8-OH-DPAT

9 1 87

7 8 (cq) 6 9 (ct2)

0.01-1 0 0 05-4 0

58 36, 55, 74

Partial Agomsts BMY 7378* Ipsaplrone* Busptrone* Gepirone* NAN 190" MDL 73005*

86 77 75 7 1 92 8.6

7 0 (D2), 6 7 (a t) Selective 6 5 (D:) Selective 9 1 (a t ) Selective

0 05-0 5 0 5-20 0 0 5-20 0 0 5-20 0 0 03-3 5 0 3-3 0

13,80 28 25,59 25.36 30, 31, 35 59

Antagomsts ( __.)-Cyanopmdolol ( - )-Pmdolol Spiperone Memepm ( - )-Propranolol

8.3 7.7 72 7 1 68

10 4 (13), 8 3 (5-HTIa) 8 8 (13), 7 8 (5-HTta) 9 4 (D2), 8 5 (5-HTz), 7 6 (ct t) 8 9 (at), 8 2 (5-HT2), 8.0 (D 2) 8 7 (13), 7 3 (5-HTta)

unknown 0 5-4.0 0 025-0 25 0 05-0 2 1 0-16 0

26,27 2, 36, 74 36, 50, 74 36, 50, 74 2, 36, 74

pK o is -logto affimty of drug for radiohgand binding site Dose range is mg/kg by systemic mjectton MDL 72832 8-[4-(l,4-benzodtoxan-2-ylmethylammo)butyl]-8-azasptro[4,5]decane-7,9-dlone,8-OH-DPAT, 8-hydroxy-2-(dl-n-propylammo)-tetrahn, BMY 7378 8-[2-[4-(2-methoxyphenyl)-I-piperaz,nyl]ethyl]8azasptrol[4 5]-decane-7,9-dlone, NAN 190 I-(2-methoxyphenyl)-4-[4-(2-phthahmmldo)butyl]plperazme

siderable affinity for the 5-HT 2 receptor (Table 3). A key objective in this area is again the identification o f selectwe compounds. 5-HTtD RECEPTOR AGONISTS AND ANTAGONISTS The 5-HTtD r e c o g n m o n site was first identified m 1987 by H e u n n g and Peroutka as those 5-HT I binding sites remaining in

the calf caudate after the blanking out o f 5-HTIA and 5 - H T , c receptors (33) Subsequent work has established that the 5-HTtD receptor, which IS found in most higher species including man, is the equivalent o f the 5-HTIB site in the rat and mouse m terms o f its location and functional correlates (38). Relatively few 5-HT,D receptor agonists have been identified (Table 4). 5-CT is the most powerful 5-HTtD receptor agonlst, but it shows poor

TABLE 2 5-HTm RECEPTOR AGONISTS AND ANTAGONISTS

5-HTtB pK D Agomsts RU 24969 CP-93, 129 CGS 12066B MCPP TFMPP

8 7 7 6 6

2 8 3 5 9

Antagonists ( _ )-Cyanopmdolol Metltepm ( - )-Pmdolol ( - )-Isamoltane Propranolol

8 7 7 7 7

3 3 8 7 3

Other Activity pK D

Dose Range In VIvo (mg/kg)

7 9 (5-HTIA) 2 5-10 5 7 (5-HTIA) 0 016 (mg, IA) 6 1 (5-HTtA), 7.5 (5-HTtD) 4.5 7 8 (5-HTtc), 7 3 (5-HT3L 6 6 (5-HTtA) 1-20 7 3 (5-HTtc), 6.5 (5-HTIA), 6.6 (5-HTID) 1-20 10 4 (13), 8.3 (5-HT,A) 8 9 (al), 8 2 (5-HT2), 8.0 (D 2) 8 8 (13), 7 7 (5-HTIA) 8 1 {13) 8 7 (13), 6 8 (5-HT~A)

4 0-8 0 0 25-1 0 0 5--4 0.3-3 0 1-16

References

9,75 54 60,67 43, 47, 67 44, 67, 43 26, 27, 44, 43 12, 36, 50 2, 36, 44, 75 79 2.36, 75

pKD is - logto affimty of drug for radtohgand bmdmg site Dose range ~s mg/kg by systemic m.lectlon RU 24969 5-methoxy-3 (1,2,3,6-tetrahydropyndm-4-yl) IH mdole, CP-93,129 3-(l,2,5,6-tetrahydropynd-4-yl)pyrolo[3,2-6]pynd-5-one, CGS 12066B 7-tnfluoromethyl-4 (4-methyl-l-plperazmyl-pyrolo[1,2-a]qumoxahne, MCPP metachlorophenylp~perazme, TFMPP tnfluoromethylphenylp~perazme

78

MIDDLEMISS AND TRICKLEBANK

TABLE 3 5-HTic RECEPTOR AGONISTS AND ANTAGONISTS

5-HTjc pKD

Other Activlty pKD

Dose Range In Vlvo (mg/kg)

References

Agomsts MCPP TFMPP MK-212

78 73 62

7 3 (5-HTa), 6 5 (5-HTm), 6 6 (5-HTIA) 6 9 (5-HTta), 6 6 (5-HTIA), 6 6 (5-HTtD) 5 3 (5-HTIA), 5 0 (5-HTm)

1-10 5 0 5-10

42--45, 47, 67 43, 45, 67 36.48

Antagomsts Mesulergme Ritansenn I-NP M~ansenn Metitepm

8.8 86 8.2 80 76

8 4 (5-HT 2) 9 3 (5-HT2) 7 2 (5-HT2); 7 2 (5-HTIA) 7 5 (¢tz), 8 1 (5-HT2) 8 9 (cq), 8 2 (5-HT,); 8 0 (D2)

02 >0 6 0 5-5 2-5 Unknown

36, 42, 45 36,45 36, 42, 45 36, 45, 65 36,50

pKD is -Iogto affimty of drug for radmhgand binding site Dose range is mg/kg by systemic mjecnon MCPP metachlorophenylplperazme, TFMPP tnfluoromethylphenylplperazme, I-NP I-(1-naphthylplperazme)

selectivity and, because of ~ts profound cardiovascular effects (17), is a difficult drug to use for behavioural studies, Sumatriptan is a more selective, albeit somewhat weaker agonist, but does not penetrate the CNS after systemic admmlstratmn. RU 24969 readily penetrates the CNS, but ~s nonselective and the systemic dose needed to activate the central 5-HT~t) receptor remains to be established As yet no specific 5-HT~D receptor antagonists have been identified and the currently known blockers, metergohne and metltepm, are not good tools to use m vivo (Table 4). Undoubtedly, the development of both specific agonists and antagonists for the 5-1-ITID receptor will be the focus of much attention over the coming years in the light of the activity of sumatnptan in amehorating the symptoms of migraine (22) 5.HT: RECEPTOR AGONISTS AND ANTAGONISTS The hallucinogen, lyserglc acid dlethylamide (dLSD), has been proposed as a potent 5-HT 2 receptor agomst, but has no

selectivity with respect to other 5-HT receptors (Table 5). A number of 4-substituted 1-(2,5-dunethoxyphenyl)-2-armnopropanes such as DOM (4-methyl), DOB (4-bromo) and DOI (4-1odo) are also potent 5-HT 2 receptor agomsts, but show only limited selectivity with respect to the 5-HT1c receptor. The degree of selectivity seen with this class of agonist appears to depend crucially on the radlohgand used to label the receptor. Thus, in Table 5 the data are taken from studies using the antagonist radiohgands, [3H]-ketansenn and [3H]-mesulergme, whereas an apparent selectivity for the 5-HT~c receptor for DOI can be demonstrated if the ligands used are [3H]-5-HT (5-HTIc) and [3H]-splperone (5HT 2) (77). Clearly, the functional consequences of activation of receptors by aminopropanes could be medmted by either 5-HT 2 or 5-HT~c sites and careful studies with selective antagonists are needed to resolve this conundrum Although many 5-HT 2 receptor antagonists have been developed, only MDL 11,939 [(11,23) and M. G. Palfreyman, personal communication], ketansenn and sptperone may be of low enough affinity for the 5-HTtc site to

TABLE 4 5-HT~D RECEPTOR AGONISTS AND ANTAGONISTS

5-HTtD pKo

Other Activity pKD

Dose Range In Vwo (mg/kg)

References

Agomsts 5-CT Sumamptan RU 24969

86 78 73

9 5 (5-HTIA), 8 3 (5-HTla) 7 6 (5-HTta), 7 0 (5-HTtA) 8 2 (5-HTm), 7 9 (5-HTIA)

0 004--0 025 (mg, IC) 0.01-0 025 (mg, IC) Unknown

34,36 34,64 36

Antagon|sts Metergohne Met~tepm

9 1 82

9 2 (5-HTc), 9 0 (5-HT2), 8 1 (5-HT,A) 8 9 (ct,), 8 2 (5-HT2), 8 0 (D2)

5-10 1

33, 34, 36 34, 36, 50

pK D Is - log m affinity of drug for radlohgand binding site Dose range ts mg/kg by systemic rejection, unless stated otherwise IC mtracerebral 5-CT 5-carboxamldotryptanune, RU 24969 5-methoxy-3 (l,2,3,6-tetrahydropyndm-4-yl) 1H lndole

5-HT RECEPTOR AGONISTS AND ANTAGONISTS

79

TABLE 5 5-HT~ RECEPTORAGONISTS AND ANTAGONISTS

5-HT2 pKD Agonlsts dLSD DOI DOB DOM

86 77 7.2 7.0

Antagonists Ritansenn Ketansenn Sergolexole Methyserglde Mlansenn MDL 11,939 ICI 169,369

93 8.9 87 86 8 1 83 7.8

Other Activity pKD

8 6 (5-HTIA), 8 2 75 72 67

(5-HTID), 7 9 (5-HTlc) (5-HTlc) (5-HTIc) (5-HTIc)

8.6 (5-HTjc) 8 0 (eq), 8 0 (H 0 8 5 (5-HTIc) 8 6 (5-HTIc), 8 4 (5-HTID) 8.0 (5-HT~c), 7 5 (ct2) 6 4 (eq), 6 2 (5-HTic), 6 0 (5-HTtA) 8.0 (5-HTic), 6 3 (eq),

Dose Range In Vlvo (mg/kg)

References

0 04-0 06 0 1-0 5 0 03-0.2 0 1-0 5

29,36 68,72 29, 68, 72 29, 68, 70

0 03--0 18 0 02--0 9 1-10 0 35-0 77 0 06--0 32 0 02--4 4 1-10

3,36 3, 36, 50 14 3,36 3, 36.65 11,23 3,4

pKD is -loglo affinity of drug for radlohgand binding site Dose range is mg/kg by systemic reJection dLSD" d-lyserglc acid dlethylanude, DOI" l-(2,5-dlmethoxy-4-mdophenyl)-2-armnopropane, DOB: l-(4bromophenyl-2,5-dlmethoxy)-2-ammopropane, DOM 2,5-d|methoxy-4-methylamphetamme, MDL 11,939 ct-phenyl-l-(2-phenylethyl)-4-plperdme methanol), ICI 169,369 2-(2-dtmethylammoethylthlo)-3-phenylqulnohne

be useful in this respect. The latter two drugs, however, display high affinity for eq-adrenoceptors and other receptors which makes interpretation of their effects in VlVOsomewhat ambiguous 5-HT3 RECEPTORAGONISTSAND ANTAGONISTS While the lack of selectwe 5-HT receptor antagonists is a problem for evaluating the functional roles of 5-HT~ and 5-HT2 receptors, this ~s not the case for the 5-HT 3 subtype. Potent and

highly selective antagonists include MDL 72222, ondansetron, granisetron and ICS 205-930. The extremely low doses at which these compounds Induce behavtoural change (Table 6) indicates that the compounds readily penetrate the CNS after systemic administration. Unfortunately, brain penetration is a problem for the few 5-HT 3 receptor agonists (2-methyl-5-HT, phenylbiguanlde and its much more potent analogue, metachlorophenylblguamde) that have, so far, been identified. Subtypes of the 5-HT 3 receptor have been proposed on the

TABLE 6 5-HT3 RECEPTORAGONISTSAND ANTAGONISTS

5-HT3 pKD

Other Activity pKD

Agonlsts 2-Me-5-HT M-Chloro-phenyl-blguanlde

7 1 95

5 8 (5-HTIc), 5 6 (5-HTtA) Selectwe

Antagonists MDL 73,147 Granlsetron Zacopnde ICS 205-930 Ondansetron MDL 72222

9 8* 9.2 87 85 85 7.3

Selective Selective Selective Selective Selective Selective

Dose Range In Vivo (mg/kg)

1-10 (ng,ICV) unknown 0 5-5 0 00001-0 0.0001-0 0 00001-0 0 001-1 0 001-0

001 1 01 0 1

References

20, 27, 47 46 71 19,47 1,18 19,47 41,47 47,76

~'pA2 m rabbit heart preparation pKo is -loglo affinity of drug for radlohgand binding site Dose range is mg/kg by systemic injection. MDL 73,147 lH-indole-3-carboxyhc acld-trans-octahydro-3-oxo-2,6-methano-2H-qulnohzlm-8-yl-ester methanesulphonate, ICS 205-930 3 tx-tropanyl-lH-lndole-3-carboxyhc acid ester, MDL 72222 3-tropanyl3,5-dlchlorobenzoate

80

MIDDLEMISS AND TRICKLEBANK

basis o f the wide & s c r e p e n c y m potencies o f ICS 205-930 and its analogues, c o m p o u n d I and c o m p o u n d II, at 5 - H T 3 receptors in the rabbit heart, rat v a g u s and g u i n e a pig ileum (66). M o r e recent studtes suggest, however, that the potency differences m a y be species-specific, 1.e , the low affinity in the guinea pig ileum is reflected in a stmilarly low affinity in the guinea pig v a g u s (10). It r e m a i n s to be seen w h e t h e r the guinea pig 5 - H T 3 receptor Is f u n d a m e n t a l l y different from that In the rat or m a n A further a n o m a l y that m a y reflect the existence o f 5 - H T 3 receptor subtypes concerns the stereoselectlvity o f the 5 - H T 3 receptor antagonist, z a c o p n d e . R( + ) - Z a c o p r i d e is more than 100fold more potent than the S ( - ) - e n a n t l o m e r in the light/dark box test o f anxlolytlc activity (81), although S ( - )-zacopnde is 10-40 fold more potent against [3HI-( _+ )-zacopnde binding (equivalent

tO the 5 - H T 3 recognition site), in the rabbit v a g u s and m animal m o d e l s o f e m e s l s (78). T h e site and m e c h a n i s m o f action o f zacopride m these anxiolytic tests is thus enigmatic. CONCLUSIONS Functional and receptor binding studies o f the actions o f 5 - H T receptor a g o m s t s and antagonists have led to claims o f no less than 11 s u b t y p e s o f 5 - H T receptor. O f these 5 have been positively differentiated by receptor cloning and purification. A t t e m p t s to identify receptor selective drugs have so far y~elded selective agonists for 5-HTIA, 5 - H T l a and 5 - H T 3 receptors and selective antagonists for 5 - H T 2 and 5 - H T 3 receptors. Clearly, 5 - H T receptor p h a r m a c o l o g y is only m tts infancy.

REFERENCES 1 Barnes, N M . Costall, B , Naylor, R J [3H]Zacopnde Ligand for the ~dentlficatlon of 5-HT 3 recogmtmn sites J Pharm Pharmacol 40 548-551, 1988 2 Beer, M , Richardson, A , Poat, J . lversen, L , Stahl, S M In vitro selecnvlty of agomsts and antagomsts for betas- and beta2adrenoceptor subtypes m rat brain Biochem Pharmacol. 37 11451151. 1988 3 Blackburn, T P , Cox, B , Thomber, C W . Pearce. R J Pharmacological studies m vwo with ICI 169,369 a chemically novel 5-HT2/5-HT~c receptor antagomst Eur J Pharmacol 180 229-237, 1990 4 Blackburn, T P , Thornber. C W . Pearce, R J , Cox. B. In vitro stu&es with ICI 168,369, a chenucally novel 5-HT antagomst Eur J Pharmacol 150 247-256. 1988 5 Bobker. D H , Williams, J T Ion conductances affected by 5-HT receptor subtypes m mammahan neurons Trends Pharmacol Scl 13 169-173, 1990 6 Bouhelal. R , Smounya, L , Bockaert, J 5-HT m receptors are negatwely coupled w~th adenylate cyclase in rat substantm mgra Eur J Pharmacol 151 189-196, 1988 7 Bradley, P B , Engel, G , Femuk, W . Fozard. J R , Humphrey. P. P A , Mlddlemlss, D N . Mylecharane, E J , Richardson, B P , Saxena. P R Proposals for the classification and nomenclature of funcnonal receptors for 5-hydroxytryptamme Neuropharmacology 25 563-576. 1986 8 Branchek. T A , Wemshank. R L , Macchl. M J . Zgomblck. J M Cloning and expression of a human 5-HT~t) receptor Second IUPHAR Satellite on Serotonln 2 1990 9 Brazell. M P , Marsden. C A , Nlsbet. A P , Routledge. C The 5-HT~ receptor agomst RU-24969 decreases 5-hydroxytryptarmne (5-HT) release and metabolism m the rat frontal cortex m vitro and m vtvo Br J Pharmacol 86209-216, 1985 10 Burndge, J . Butler. A , Kdpatnck, G J 5-HT3 receptors mediate depolansanons of the guinea-pig isolated vagus nerve Br J Pharmacol 96 269P, 1989 11 Carr, A A , H a y , D A , D u d l e y , M V . Nteduzak. T R Denvatwes of MDL 11,939 as highly potent and selective mhthltors of serotonm 5-HT: receptors Second IUPHAR Satelhte Meeting on Serotonm PI80, 1990 12 Chaput. Y , Bher, P , De Montlgny. C In vwo electrophyslologlcal evidence for the regulatory role of autoreceptors on serotonergtc terminals J Neuroscl 62796-2801. 1986 13 Chaput. Y . De Montlgny, C Effects of the 5-hydroxytryptamme t receptor agomst, BMY 7378, on 5-hydroxytryptamme neurotransmission Electrophyslolog~cal stu&es m the rat central nervous system J Pharmacol Exp Ther 246 359-370, 1988 14 Cohen, M , Fuller. R W , Kurz, K D , Parh, C J . Mason, N R , Meyers, D B , Smallwood, J K , Toomey. R E Prechn~cal pharmacology of a new type of serotonerglc receptor antagomst, LY281067 J Pharmacol Exp Ther 244 106-112, 1988 15 Conn. P J , Sanders-Bush. E Selectwe 5HT-2 antagomsts mh~blt serotomn stimulated phosphandyhnosltol metabohsm m cerebral cortex Neuropharmacology 23 993-996. 1984 16 Conn. P J , Sanders-Bush, E Agomst reduced phospho.nosmde

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NOTE ADDED IN PROOF Bjork et al (J Pharrnacol Exp Ther 258 58--65, 1991) have described the pharmacological properties of 5-OH-301 and shown it to be a selective 5-HTjA receptor antagomst and Mancq et al (Science 254 432--437, 1991) have described the molecular clomng of the 5-HT3 receptor

Centrally active 5-HT receptor agonists and antagonists.

Eleven subtypes of central 5-HT receptor have so far been postulated, four of which have been cloned (5-HT1A, 5-HT1C, 5-HT1D and 5-HT2) and a fifth (t...
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