Brit. J. Anaesth.

(1962), 34, 260

A REVIEW OF THE CHEMICAL FEATURES ASSOCIATED WITH STRONG MORPHINE-LIKE ACTIVITY

BY PAUL A. J. JANSSEN

From the Research Laboratorium Dr. C. Janssen (Beerse, Belgium) In spite of quantitative differences known to narcotic properties, whereas others are relatively exist and that are, not infrequently, quite im- unimportant.(6' 16) portant in medical practice, all morphine-like (A) Certain stereochemical features are very narcotics have a certain number of properties in important: the mirror image, (+)-morphine, is common. All potent narcotics will produceat devoid of analgesic activity and all known partial least to some degree and at varying dose levels structures related to morphine that are potent relief from pain, respiratory depression, emesis, narcotics have certain important stereochemical constipation, physical dependence, sedation in features in common (see further).(9) man, dogs, rats and monkeys, excitation in mice, (B) The C-ring of ()-morphine is a sixcats and horses, miosis in man, mydriasis in membered ring of carbon atoms (cyclohexene), mice, etc. Their respiratory depressant effects are extending below the plane of ring B (fig. 1), effectively antagonized by small doses of nalorphine having a double bond between C 7 and C 8 and a and their emetic effects by potent neuroleptic free hydroxyl group below its plane in C6. All drugs such as Haloperidol or chlorpromazine. these features are relatively unimportant. The spectrum of these properties is so typical and homogenous that it appears safe to presume that all potent narcotics exert their effects by a common mechanism of action. If this is true, then it appears reasonable to look for chemical features that are associated with morphine-like activity, particularly among narFIG. 1 cotics producing their effects at low dose levels. ()-Morphine (absolute configuration and conformation). There might indeed exist something like a common specific receptor area, somewhere in the (Ba) Removal of the G-OH group and saturation brain, possibly in the thalamic area, to which a of the double bond leads to ()-desomorphine-D narcotic molecule must be able to fit before it can (fig. 2), the simplest C-ring variant of morphine, act. No one has ever demonstrated this hypotheti- which is roughly ten times more potent than cal area, of course, and there is no serious reason morphine itself.(6) Its C-ring is a chair, thus to believe that anyone will be able to do so in the demonstrating the relative unimportance of the near future. We might, therefore, try to approach boat-conformation of the C-ring of morphine. the problem from the opposite angle and ascertain to what extent molecules with powerful narcotic properties look alike chemically. The three-dimensional structure of figure 1 represents the absolute configuration and conformation of the laevorotatory natural alkaloid ()-morphine. Certain chemical features of this s rather complicated five-ring (rings A to E) FIG. 2 T-shaped molecule (D-ring above and C-ring (>Desomorphine-D below the plane of the paper) are important for its (absolute configuration and conformation). 260

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CHEMICAL FEATURES ASSOCIATED WITH MORPHINE-LIKE ACTIVITY (Bb) A large series of other C-ring variants of morphine has been synthesized. Many of these structures are potent narcotic analgesics (table I).
TABLE I "C-ring" variants of morphine. TABLE II

261

Methylation of the 3-OH group in ()-morphine or its C-ring-variants produces ()-codeine or other 3-OCH,derivatiyes of these C-ring-variants. The phenols are 105 times more potent as analgesics than the corresponding methyl ethers, as shown by the following data.11' ' '* Name OH OCH, OH OCH, OH OCH, OH OCH, Morphine Codeine -Isomorphine -Isocodeine Dihydro- -isomorphine Dihydro- -isocodeine Dihydromorphine Dihydrocodeine (paracodine*) Morphine = 1 1.0 0.15 0.05 0.9 0.3 0.20.15 2.0 1.0 0.3 0.1 2.5 1.5 0.2 0.1 1/13
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Only the chemical structure and the probable conformation of the C-ring are shown, the rest of the molecule being identical with morphine, including the stereochemical features. All these compounds are typical morphine-like narcotics; their potency (P.R.) is expressed in terms of morphine = l."' 1 4 )

Ratio 1/6 1/5

1/7

a=OH, p=H: (>morphine(P.R. = 1). ot=H, p=OH: a-isomorphine(P.R. ~ 1).

a=OH, p=H: dihydromorphine or paramorphan (P.R.=21). a = H , P=OH: dihydro-isomorphine (P.R.=2 1). a = p=H: desomorphineD, P.R. = 8-53-5. a=OCH,, P=H: dihydrohetero-codeine: P.R. = 40-5.

OH OCH, OH OCH, OH OCH, OH OCH,

Dihydrohetero-codeine 4.0 0.5 Dihydro, methyl ether 0.7 0.2 Hydromorphone Hydrocodone (dicodid*) Desomorphine-D Desocodeine-D Oxymorphone Oxycodone (encodal*) 5.0+2.0 0.7 0.1 8.5 3.5 0.60.2 11 3.0 2.0 1.5

1/6 1/7

1/14 1/5

5 = 14 = H: hydromorphone or Delaudid: P.R.=5 2. 5=CH,; 14 = H: metopon: P.R.=74. 5 = H; 14=OH: oxymorphone or Numorphan : P.R. = 1I3.

Methyldesorphine or MK-57: P.R. = 9 3 .

(C) The free phenolic hydroxy-group of morphine and its C-ring-variants cannot be muzzled with an alkyl group (e.g. a methyl-group; producing a CH3O-ether like in codeine) without greatly reducing analgesic potency (table II). Higher analogues of codeine (e.g. ethylmorphine or benzylmorphine) become increasingly inactive, whereas acetylation of the phenolic OH-group in position 3 of morphine and its C-ring-variants (e.g. diacetylmorphine or heroin) is compatible

with very high analgesic potency. All other known chemical changes on the aromatic ring have invariably produced very striking loss of activity.15-16) (D) The secondary amine normorphine (replacement of NCH 3 by NH) as well as all other known secondary or quaternary amines derived from five-ring T-shaped molecules related to morphine are either inactive or very weak analgesics. Replacement of the NCH3 moiety by other chemical groups (NR) reduces analgesic activity as a rule, but there are a few important exceptions. For example, ()-N-2-phenetylmorphine is about 15 times more potent than ()morphine itself<.16) (NCHj CHj Q H6). Replacement of this methyl-group by a few other groups of low molecular weight may even produce potent antagonists of morphine-like compounds. Nalorphine or N-allyl-normorphine (CH3 replaced by allyl or CH2CH=CH;>) is the classical prototype of these antagonists.15- 15 - 16)

262 Thus the C-ring of morphine possesses at least a few relatively unimportant chemical features. Moreover, the E-ring or the ether linkage between rings A and C is also a "useless complication" in the ()-morphine structure. Its removal from ()-desomorphine-D or its N-R derivatives actually leads to the four-ring ()-morphinans (fig. 3) that are, as a rule, more potent than the corresponding five-ring structures from which they are derived. The active morphinan-isomers have all the same configuration as ()-morphine, the mirror image of the isomers shown in figure 3 being inactive or very weak. Removal or alkylation of the OH-group in C3 again reduces potency.*4- " 7>10) Dextromorphan or RomilarR, (+)-3-CH 3 O-N-CH 3 -morphinan, is said to be an antitussive compound with very little analgesic activity, its mirror image a weak narcotic. The morphinans are ring B/ring C- cis structures. A few B/C- trans isomers have been prepared (iso-morphinans, fig. 4) and, surprisingly, found to be somewhat more potent than the corresponding isomeric morphinans.<8) The unknown B/C- trans isomer of ( )-morphine may therefore, by analogy, be suspected to be more active than ()-morphine itself.

BRITISH JOURNAL OF ANAESTHESIA

O-ring
C ring

FIG. 4 The skeleton of the iso-morphinans."1

The high potency found among several members of the benzomorphan-series (fig. 5) shows again the relative "unimportance" of at least some chemical features of the C-ring in the 4- and 5ring structures already described, but further removal of part of the C-ring (e.g. removal of one or both methyl-groups attached to ring B of metazocine or phenazocine) reduces activity.16- M
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CH3

FIG. 5 Absolute configuration of the CH,/CH,-cis and -trans isomers of the benzomorphan-series (potency: morphine = 1); cis, L=CH,: ()-metazocine (potency =1); cis, L = CH,CH,C,H6: ()-phenazocine (potency=20). The trans-isomers are more active than the corresponding cis-isomers; methylation or removal of OH reduces activity. The mirror images have very low potency."' Ul
-CH2

R CH,

'otency 8 20

Name Levorphanol

CH.CH./ CH.-C^

rlnflC

>

()-Phenomorphan
FIG. 6 Essential chemical features and absolute configuration of the 3-, 4- and 5-membered potent narcotics derived from ()-morphine, and shown in figures 1 to 5. IU)

100

Levophenacyl-morphan

CH.CH, ^ CH,CH=CH,
H

200 low low

Levallorphan (potent antagonist) Norlevorphanol

FIG. 3 Analgesic potency (morphine= I) of the ()-morphinans (absolute configuration as shown).'71

Figure 6 therefore depicts the essential chemical and stereochemical features associated with high activity among these compounds, i.e.: (a) An L-shaped 3-ring skeleton, consisting of a piperidine-ring to which a phenyl-ring is directly attached in position 4 (axial) and indirectly through a methylene bridge (ring B) in position 2.

CHEMICAL FEATURES ASSOCIATED WITH MORPHINE-LIKE ACTIVITY With the phenyl-nucleus to the left, the piperidine-ring extends above the place of the paper in all potent isomers. (*) A free or acetylated phenolic hydroxy-group in position 3'. to A tertiary basic nitrogen in the piperidinering, substituted with a moiety of the type CH,-X in which X is hydrogen, or, preferably, CHaQHy COCgH6, CH2-2-furyl and similar moieties. At least two further substituents on the piperidine-ring, i.e. one equatorial methylene group (CH2X) in position 4, and one similar CHjX-group in Q , preferably but not necessarily, in axial position. A second substituent in C3 (e.g. OH) is compatible with high potency, but is not required. The two methylene groups may be part of ring C.
Phenyl ring axial. Phenyl ring equatorial.

263

(-)-BetaCH3 prodine

Does not exist (aCH,)

Does not CH3 exist H (a-CH,)

CH

3 (-)-Alphaprodine

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-Betaprodine

Does not exist (aCHa)

FIG. 7 Isomer obtained by removal of the methylene-bridge of ()-metazocine.

Removal of the methylene-bridge between rings A and D in ()-metazocine (fig. 5) leads, with retention of configuration and conformation, to an isomer of 1 : 3-dimethyl-4- (3'-hydroxy) phenylpiperidine (fig. 7). This particular compound is unknown. However, the stereochemical features of a closely related series, known as the "prodines" (fig. 8), have been adequately determined. One of the optical isomers of betaprodine, probably the most potent one, i.e. ()-betaprodine, has the same stereochemical features as ()-morphine, levallorphan and ()-phenazocine.<2'3) This isomer, therefore, may be said to "imitate" most of the typical chemical features of ()-morphine. Unlike the other narcotics discussed thus far, however, a prodine is not a "partial structure" related to morphine. A very large series of related two-ring derivatives of 4-phenylpiperidine has been prepared, and pharmacological investigation has shown that the general structure of figure 9 represents the most potent narcotics found in this general series. The prototype of these simple 4-phenyl-piperidines is pethidine or meperidine

Does not "H3 exist H (aCH3)

FIG. 8 Stereochemistry and conformation of the four optical isomers of 1 : 3-dimethyl-4-phenyl-4-propionoxy-piperidine (P=OCOC,H,), known as the "prodines". ()-Betaprodine is several times more potent than ()-alphaprodtne or ()-morphine. In each racemate, one optical isomer (probably the ()-isomer) is many times more active than the other."' "

Umibttlmtcd boncncrinj

CHOH or CO of NH of oxyicii or CH. (or cjonnnrO H or lower iftyt or tllyl-

FIG. 9 Chemical features associated with maximal analgesic potency among "simple" 4-phenylpiperidine-derivatives (conformation largely unknown).'1' ''

264 (fig. 10), the first synthetic narcotic, described in 1939 by Eisleb and Schaumann. In figures 10, 11 and 12 the relationship between the structure of pethidine-like compounds and analgesic activity is briefly illustrated.'' 6- " 1 2 - 1 3 . 1 6 ) Maximal analgesic potency among these drugs is associated with the following chemical features.'1'131 (a) An unsubstituted phenyl nucleus (or an isosteric ring such as thiophene) attached to the basic nitrogen atom of the piperidine ring by an unbranched chain of three atoms (figs. 9 and 10). (b) A substituent of the type R-CHjCH 2 in position 4 of the piperidine ring (R=OCO, COO or COCH,), consisting of a straight chain of 4 carbon atoms or of 3' carbon- and one oxygen-atom (figs. 9 and 11). (c) The presence of a phenolic OH-group is not required for high potency (fig. 12). Other substituents on the phenyl-nucleus generally decrease activity. (d) A suitably selected and stereochemically arranged substituent X in position 3 of the piperidine ring (e.g. methyl or lower alkyl) may have a potency-increasing effect. The
TABLE

BRITISH JOURNAL OF ANAESTHESIA conformation of X is probably equatorial and the most active optical isomers are probably stereochemically related to ()-betaprodine (fig. 8). (e) All attempts to increase the analgesic potency of pethidine-like compounds by isomeric replacement of its typical substituents from position 4 to position 3 or 2, or by increasing or decreasing the size or further substitution of the piperidine-ring have only produced less active or inactive narcotics (e.g. ethoheptazine or zactirin, trimeperidine, promedol and isopethidine). The well-known 3 : 3-diphenylpropylamines related to methadone (structure 3 in table III) constitute another, chemically somewhat related class of narcotics. Table III illustrates how the piperidine ring of pethidine-like drugs can be "opened" to produce the analgesically very weak derivatives of 3-phenyl-butylamines (2 in table III; e.g. propoxyphene). Replacement of the last carbon atom in 2 by a phenyl ring, however, produces 3 : 3-diphenylpropylamines. Inspection of table III gives a rough idea of the chemical features (R, a, p, NAA') associated with high analgesic activity in this series.<1J) Branching of
HI

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Illustration of the chemical relationship between the pethidine-(l) and the methadone series (2), and analgesic potency in man (morphine=l) of a representative series of 3 : 3-diphenylpropyl-amines related to methadone (3). (1JI nan

N- C - C - C - C

i.J -CH-CH-C
(3) d,l dl dl dl dl d Potency 2 1 1 2 2 low 4 Name Methadone, amidone (Polamidone*; Isomethadone Normethadone (Ticarda*) Dipipanone (Pipadone*) Phenadoxone (Heptazone*) Dextromoramide (Palfium* R875)

(0 R
COCH.CH, COCH.CH, COCH.CH, COCH.CH, COCH.CH, COOC,H5
CON

(2)
a

NAA' N(CH,), N(CH,), N(CH,). Piperidine

Morpholine Morpholine Morpholine

P
CH, H H CH, CH, H H

H CH, H H H H CH,

OCOCH, CH CH.CH, N (CH,), CH CH.CH, N (CH,), Piperidine CONH,

CN OH H Piperidine Piperidine Piperidine

H H H

H
H H

CH, CH, H H H H

adl

p-di

0 0 0 0

Alphacetylmethadol Betacetylmethadol Very potent atropine-like drug Potent atropine-like drug Weak atropine-like drug Aspasan*

o
L C-OCH.CH,

L=CH, : pethidine : 25-150 mg. OH

L = / VcH-CH,CH,- : phenoperidine
O

(R 1406): 0.25-2 mg.

j - : R 951 : 0.50-3 mg. L=f ~>CH,CH,- : pheneridine : 10-50 mg. V c H . C H , - : anileridine (Lerituie): 10-50 mg.
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L=H,N-/
N

=/

L=^f / \NH-CH,CH,CH,- : piminodine (Alvodine) \= 10-40 mg. L=HO-CH,CH,-O-CH,CH,- : ctoxeridine (Atenos): ~ 75 mg. FIG. 10 Structure and usual clinical dose range (in mg per 70 kg body weight) of some analgesically active 4-phenylpiperidines derived from norpethidine (i=H). ( t ' " ">

CH^N "X

,v /R-alk O O O

R OH _^_ nihil 0 0 CH
ooooo

alk

H CH, CH.CH. CH,CH|CH|CH!

() pethidine () bemidone

s. ketone ether alcohol alkyl FIG. 11 Replacement of the carbethoxy-group (COOC,H,) in pethidine by other moieties of the type R-alkyl has the following effects on analgesic potency.11'1"

"reversed" ester

t
R R R

+
"straight" ester

CH 3 N \ OCO.C.H, COO.QH, CO.CH, CH.QH,

X = H

OH i : hydroxypethidine ketobemidone (Cliradon )

R =

Fro. 12 Introduction of a phenolic OH-group in meta-position has the following irregular effects on analgesic potency of pethidine-like narcotics."1"

266
the side chain in a or p with a methyl-group produces a pair of optical isomers of which one, as a rule, is twice as active as the racemate, the other virtually devoid of analgesic activity. The most active narcotic of this series is Dextromoramide (Palfium*, R 875). Substitution of the phenyl-rings, shortening or lengthening the ethylene side chain as well as the substituents R of table III results in great loss in activity. An interesting recent development shows that high morphine-like potency may be associated with the presence of a secondary amine group, monomethylamines related to the acetylmethadols (table III) being highly active narcotics. The highly active narcotics considered thus far are all I 3-phenylpropylamines of the type CgHg-C-CHI I CH-N-CHj-. The carbon atom attached to the I phenyl-group can, however, be replaced by nitrogen to yield 2-anilinoethylamines of the I general type QHu-N-CH-CH-N-CHj-. Figures I I I 13 and 14 illustrate the possibilities of obtaining highly active narcotics of this general structure.

BRITISH JOURNAL OF ANAESTHESIA Much less is known about the relationship between chemical structure and morphine-like potency of ethylenediamine derivatives related to the structures of figures 13 and 14, than about the compounds derived from 3-phenyl-propylamine, discussed above. Recent findings in this laboratory revealed the extremely high narcotic potency of certain 4-anilino-piperidines (fig. 15). In these surprisingly active compounds, the phenyl ring, attached to the piperidine nucleus through a nitrogen atom, is separated by a chain of 4 atoms from the basic nitrogen, whereas in all the other potent narcotics, previously discussed, this chain consists of only three atoms.

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N-C-CH 2 CH 3

FIG. 15 Compound JR. 4263, the extremely potent (up to 5,000 times morphine) prototype of a new series of 4-anilinopiperidines.'"

HCH

A \)

fand as morphine.1"

FIG. 13 Two derivatives of 2-anilinoethylamine: phenampromid

and diampromid, respectively as active as pethidine

There are a few more prototypes that should be briefly discussed before making an attempt to draw general conclusions. The first is Pirinitramide or R 3365 (fig. 16), a potent analgesic with relatively little physical dependence producing capacity, in which the phenyl-ring attached to the piperidine-nucleus in 4-phenyl-piperidine-derivatives, is replaced by a second piperidine-ring.(11)

OC 2 H 5

FIG. 16 Piritramide (R 3365; 1 to 4 times morphine), the prototype of a series of 4-amino-4-carbanimaylpiperidines."1'

14 Another derivative of 2-anilinoethylamine, the prototype of a series of benzimidazol derivatives with very high potency (up to 1,000 times morphine)."1 Noticeable features: the nitro-group, enhancing activity considerably; the diethylamino-group, a rare moiety among potent narcotics.
FIG.

Another type of narcotics that is produced by isosteric replacement is the thiambutine-series (fig. 17). These dithienylbutenylamines are obviously related to the 3 : 3-diphenylpropylamines of which methadone is the prototype (table III).

CHEMICAL FEATURES ASSOCIATED WITH MORPHINE-LIKE ACTIVITY

267

i
A'-'

FIG. 17 The thiambutene series (potency: up to 2 times morphine).

The spiro-compounds of figure 18 were recently prepared in this laboratory and found to be extraordinarily potent and much longer acting (several days) than any other narcotic described thus far. These compounds are obviously related to the methadone-type as well as to the pethidine-

type of narcotic drugs (table III and figure 9).(1) In recent years a large number of relatively weak morphine-like narcotics have been described and studied. These data, however, are of very limited usefulness in connection with the structureactivity problem discussed in this paper and can' therefore not be discussed in this short review. Figure 19, summarizing the relevant data discussed in this paper, represents the common stereochemical features found among the compounds that are known to display typical morphinelike properties at low dose levels. Because these molecules look alike chemically, it appears reasonable to assume that there might be something like a common receptor for morphine-like drugs.
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-CH 2 CH 2 REFERENCES

FIG. 18 Spiro-compounds related to diphenoxylate. High morphine-like potency. Very long duration of action.11

L m phenyl or bonencring(Lt connected to N ts follows' L- CH, CH,. V CH, CH, CH,. I-tCCH, CH_ LtHOHCH, CH_ L-NHCH, CH,. LOCH, CH.. LCH-CHCH,. L"C. H. CX CH. CH. (X-CO ilk. CN.HI or L . H .

-? nog: morpboline or ppendinc. - -baitc nitrogen

-Drlng piperidlnc

NO," -

ring- cydobeure.

OH. OAc

X "central ire*' C. N or MT-fiR

E rio|. furyl, unidazoM or cjrdobcuue.

FIG. 19 Tridimensional structure representing the common chemical features associated with morphine-like activity at low dose levels. a, (3, a, b, z. 1 to 6 are carbon atoms, a', b', b " are carbon or hydrogen atoms. The small black circles are hydrogen atoms. R represents lower alkyl, OCOC,H,, COOC,H,, CHOCOCHjQH,, COC.H,, COC,H7, CONMe,, CONC4H8) or CCH,C,H4pOC,Hi.

1. Unpublished data from this laboratory. 2. Ahmed, F., Barnes, W., and Kartha, G. (1959). Configuration of the Alpha-prodine molecule. Chemistry and Industry, p. 485. 3. Beckett, A., Casy, A., and Harper, N. (1959). Configuration of Alpha and Beta prodine. Chemistry and Industry, p. 19. 4. Beckett, A., and Anderson, P. (1960). The determination of the relative configuration of morphine, levorphanol and laevo-phenazocine by stereo-selective adsorbents. J. Pharm. Pharmacol., 12, 228T. 5. Braenden, O., Eddy, N., Halbach, H., and Wolff, P. O. (1949). On pethidine and methadone derivatives. Bull. Wld. Hlth. Org., 2, 193. Braenden, O., Eddy, N., Halbach, H., and Wolff, P. O. (1954). Synthetic substances with morphinelike effect. Chemical aspects. Bull. Wld. Hlth. Org., 10, 1003. Braenden, O., Eddy, N., Halbach, H., and Wolff, P. O. (1955). Synthetic substances with morphinelike effect. Relationship between chemical structure and analgesic action. Bull. Wld. Hlth. Org., 13, 937. Braenden, O., Eddy, N., Halbach, H., and Wolff, P. O. (1956). Synthetic substances with morphinelike effect. Relationship between analgesic action and addiction liability, with a discussion of the chemical structure of addiction-producing substances. Bull. Wld. Hlth. Org., 14, 353. 6. Eddy, N. (1959). Chemical structure and action of morphine-like analgesics and related substances. Chemistry and Industry, p. 1462. 7. Eddy, N., Besendorf, H., and Pellmont, B. (1958). Synthetic analgesics aralkyl substitution on nitrogen of morphinan. Bull, on Narcot., 10, 23. 8. Gates, M., Tschudi, G. and Webb, W. G. (1956). The synthesis of morphine. J. Amer. chem. Soc, 78, 1380. Gates, M., Tschudi, G., and Webb, W. G. (1958). The synthesis and resolution of 3-hydroxy-Nmethylisomorphinan. J. Amer. chem. Soc, 80, 1186.

268

BRITISH JOURNAL OF ANAESTHESIA

9. Goto, K., and Yamamoto, I. (1957). Transformation Janssen, P., Jageneau, A., Demoen, P., van de of 1-bromosino-meneine into ( + ) morphine. Westeringh, C , de Canniere, J., Raeymaekers, Proc. Japan. Acad., 33, 477. A., Wouters, M., Sanczuk, S., and Hermans, B. Goto, K., and Yamamoto, I. (1957). Some physiologi(1959). Compounds related to pethidine. II: cal action of ( ) morphine. Proc. Japan. Acad., Mannich bases derived from various esters of 33,660. 4-carboxy-4-phenylpiperidine and acetophenones. / . Med. Pharm. Chem., 1, 309. 10. Henccka, H. (1957). Synthesis and activity of homologous morphinans. Abhandl. Deut. Akad. Wiss., p. 166. Janssen, P., and Eddy, N. B. (1960). Compounds 11. Janssen, P. (1961). Piritramide (R 3365), a potent related to pethidine. IV: New general chemical analgesic with unusual chemical structure. methods of increasing the analgesic activity of J. Pharm. Pharmacol., 13, 513. pethidine. / . Med. Pharm. Chem., 2, 31. 12. Janssen, P. (1960). Synthetic Analgesics, Part I. Oxford: Pergamon Press. Janssen, P., Jageneau, A., Demoen, P., van de 13. Janssen, P., Jageneau, A., Demoen, P., van de Westeringh, C, de Canniere, J., Raeymaekers, Westeringh, C , Raeymaekers, A., Wouters, M., A., Wouters, M., Sanczuk, S., and Hermans, B. Sanczuk, S., Hermans, B. and Loomans, J. (I960). Compounds related to pethidine. Ill: (1959). Compounds related to pethidine. 1: Basic ketones derived from norpethidine. / . Med. Mannich bases derived from norpethidine and Pharm. Chem., 2, 271. acetophenones. J. Med. Pharm. Chem., 1, 105. Janssen, P., van de Westeringh, C , Jageneau, A., 14. May, E. L., Kugita, H., and Ager, H. (1961). StrucDemoen, P., Hermans, B., Van Daele, G., tures related to morphine. XVII: Further Schellekens, K., Van der Eycken, C , and stereochemical studies with 9-oxobenzomorNiemegeers, C. (1959). Chemistry and pharmaphans. J. Org. Chem., 26, 1621. cology of C.N.S. depressants related to 4(4-hydroxy-4-phenylpiperidino) butyrophenone. Part I: Synthesis and screening data in mice. 15. Schaumann, O. (1957). Handbuch der Experimentell. Pharmakol. Springer Verlag. J. Med. Pharm. Chem., 1, 281. Janssen, P., Jageneau, A. and Huygens, J. (1959). Synthetic anti-diarrhoeal agents. I: Some 16. Winter, C , Orahovats, D., and Lehman, E. G (1957). Analgesic activity and morphine antapharmacological properties of R 1132 and gonism of compounds related to nalorphine. related compounds. J. Med. Pharm. Chem., 1, Arch. Int. Pharmacodyn., 110, 186. 299.

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BOOK REVIEW
Halothane. By C Ronald Stephen, M.D., and David M. Little, jr., M.D. Published by the Williams and Wilkins Co., Baltimore (1961). Price 4Ss. At so early a stage as the Preface the authors make it quite clear that they are aware of the intense emotional disturbance which the advent of halothane has caused among anaesthetists the world over. They assume that the truth lies somewhere between those who regard it as the universal anaesthetic and those who think it should be avoided like poison. Accordingly they attempt to separate fact from fiction, the wheat from the chaff, and present to their readers both sides of the question. They have been very successful in their self-imposed task, but it must be obvious that they would not have taken the trouble of writing a book about halothane unless they had had a favourable experience of its use. They point out that halothane is unique among anaesthetics in that it is the outcome of a deliberate attempt to find a body that was nontoxic, noninflammable and yet had anaesthetic properties. A short re'sume^ of this research of Dr. Suckling's introduces the first chapter which is concluded by Dr. Raventos's work on the absorption, distribution and elimination of halothane. The question of vaporizers is adequately dealt with. "Is your vaporizer really necessary?" is one of the questions so treated. Separate chapters are allotted to the consideration of the action of halothane on the respiratory, cardiovascular and central nervous systems as well as to its effect on the liver, kidney and other organs. Two chapters are devoted to methods of administration. The danger of putting the vaporizer in the closed circuit, especially if respiration is artificially aided, is stressed; the table on page 100, of cases of cardiac arrest, gives a number of examples illustrating this point. The book concludes with a chapter on the use of halothane in Great Britain by Dr. J. P. Payne, who expresses the opinion that halothane is a safe and reliable anaesthetic for operations outside the chest and abdomen, and with better understanding of its administration is likely soon to conquer these fields of activity. There are no less than 338 papers referred to in the list at the end. The print and paper are good and its size, 140 pages, makes it easy to handle. E. Falkner Hill