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Recent advances in pethidine-type analgesics
Sections
Replacement of the N-methyl Group of Pethidine and Related Compounds by other Groups Synthesis Reversed Esters of Pethidine Synthesis Stereochemistry Azacycloheptanes related to Pethidine Synthesis Note on Promedol The Relationship of Structure to Analgesic Activity
Details
Author: A. H. Beckett , A. F. Casy Pages: 37 to 54 Creation Date: 1957/01/01
A. H. Beckett School of Pharmacy, Chelsea College of Science and Technology, London, S.W.3 A. F. Casy School of Pharmacy, Chelsea College of Science and Technology, London, S.W.3
Synthetic analgesics including substances related to pethi-dine[1]
have recently been comprehensively reviewed by Braenden, Eddy &
Halbach (1). It is the purpose of this paper to describe important
pethidine-type compounds that have been reported since this review and
to present detailed information concerning 1:
3-dialkyl-4-aryl-4-acyloxypiperidines and 7-membered ring analogues of
pethidine. A study of structure-activity relationships in this field
will also be made.
Until recently it was thought that, for optimum activity, the basic
group of an analgesic must bear a methyl group and that substitution of
this group by higher alkyl, or other groups, must result in a fall in
activity ([1] ). That this is not the case
has
now been shown by the synthesis of several analgesics substituted by
the N-2-phenylethyl group (and other groups) that have greater
activities than the corresponding N-methyl compounds. Thus
N-2-phenylethyl- normorphine (I) and nordromoran (II) are more potent analgesics than their respective parent compounds ([2] , [3] ). Perrine & Eddy ([4] ) report that N-2-phenylethyl and N-2-hydroxy-2-phenylethyl norpethidine
(III and IV respectively, see flow sheet 2), are both at least twice as
active as pethidine. Acetylation of the hydroxy compound giving (V)
results in an almost complete loss of activity. Weijlard et al. ([5] ) have synthesized N-2- p-aminophe-nyl norpethidine (anileridine, VI) and state that it has several times the activity of pethidine. In a more detailed study, Orahovats et al. ([6]
) report that anileridine is ten to twelve times more potent than
pethidine in animals, with high oral activity and relatively mild side
reactions. May ([7]
), in contrast to the above results, has found that replacement of
N-methyl by N-2-phenylethyl in a number of morphine-fragment type
compounds (VII and VIII) results in a fall in analgesic potency.
Anderson, Frearson & Stem ([8]
), have prepared a series of pethidine analogues of type (IX) in which
Y represents an alkyl group carrying a heterocyclic residue X. Several
of these compounds show notable activity, and one, morpholinoethyl norpeth
times more potent than pethidine itself ([9] , [10] ). When oxygen is replaced by sulphur in the heterocyclic residue
Table 1
pethidine whereas compounds lacking oxygen or sulphur in
inactive.
Lengthening or shortening of the carbon chain linking the two nitrogen
atoms of the two rings results in a considerable reduction of activity;
branching also reduces activity, though not sharply.
Elpern et al. ([66] ) have recently reported an extensive series of 1-aralkyl-4-carbethoxy-4-phenylpiperidines and obtained the following results:
Replacement of the N-methyl group of pethidine by a substituted
phenylethyl group gave compounds of a potency equal to or greater than
that of the parent compound. The most potent member of this group was
N- p-aminophenyl-ethyl norpethidine, having an activity corresponding to that reported for anileridine ([6] );
Replacement of phenylethyl by pyridylethyl enhanced the potency, with 4-pyridyl being more effective than 2-pyridyl;
Lengthening the distance between the aryl group and the nitrogen
atom resulted in peak activity with three methylene groups; in the
cases of the 4-pyridyl and p-aminophenyl compounds, activity fell on increasing the chain length from 2 to 3 and with the p-nitrophenyl
compounds the 2 and 3 carbon chain compounds had similar activities
(cf. the morpholinoethyl compounds, table 1, in which a similar
increase in chain length also results in a loss of potency);
Activity was increased still further when a double bond was
included in the 3 carbon chain (the N-cinnamyl analogue is the most
active member of the whole series); peak activity in the p-aminophenyl and p-nitrophenyl
compounds was also obtained with a double bond in the carbon chain.
Activity was abolished when a triple bond was included;
Chain branching at the &beta-carbon atom (relative to the
nitrogen atom) cut activity by half, while branching at the
&alpha-carbon atom abolished activity.
Most of the compounds described in the previous section were prepared by direct N-substitution of norpethidine
(X) --an intermediate in one of the commercial methods for the
manufacture of pethidine. Flow sheet 1 indicates the synthesis of this
intermediate[2] and flow sheet 2 summarizes the synthesis of some of the compounds listed in table 1.
Reaction of the secondary base (X) with
phenylethyleneoxide gives 4-carbethoxy
1-(2-hydroxy-2-phenylethyl)-4-phenylpiperidine (IV) which on
hydrogenation gives N-2-phenylethyl norpethidine (III) and on acetylation, the ester (V). Weijland et al. ([5] ) obtained the 2- p-aminophenylethyl analogue (VI) by alkylation of norpethidine with p-aminophe-nylethylchloride hydrochloride in the presence of alkali. The compounds of Anderson et al. ([8] ) were obtained by treating norpethidine
with the appropriate substituted alkyl halide-e.g.,
2-morpholinoethylchloride to give (XI). Where this method proved
difficult (compounds 10, 13 and 14 in table 1) the secondary base was
first alkylated with ethylene chlor-hydrin and the resultant
2-hydroxyethyl compound (XII) converted into the 2-chloroethyl compound
(XIII) which reacted readily with heterocyclic bases - e.g., piperazine
to give (XIV). The majority of the compounds of Elpern et al. ([66] ) were prepared by alkylation of norpethidine with the appropriate alkyl halide; the pyridylethyl compounds were obtained by condensing norpethidine with 2- and 4-vinyl-pyridine respectively, and N-(3-phenyl-2-propargyl) ethyl- norpethidine by treatment of the secondary base with formaldehyde and phenylacetylene.
Flow sheet 1
Flow sheet 2 (Synthesis of certain of the compounds listed in table 1)
In 1943, Jensen et al. ([11] ) found that replacement of the carbethoxy group of pethidine by the propionoxy group (-OCOC 2H 5)
resulted in a fivefold increase in activity over that of the parent
compound. Independently, workers in the Roche Laboratories ([12] , [13]
) prepared many compounds of this type (the so-called "reversed esters
of pethidine ") and confirmed that the propionoxy compound (XV, R = C 2H 5) gave the most active member of the series.
The
Roche workers found that the substitution of a methyl group into the
3-position of the piperidine ring resulted in a further increase in
potency ([14] ). The compound (XVI, R = CH 3)
was obtained in two geometrically isomeric forms, designated alpha-and
betaprodine respectively, the latter isomer being resolved into its
optical enantiomorphs ([29] ) (for configuration of these isomers, see p. 44). Randall & Lehmann ([14]
) obtained the following pharmacological results in rats, morphine
being taken as 100, &alpha-form racemate 97, &beta-form
racemate 550, (+)-&beta-form 350, |( - )-&beta-form 790. In
man, the difference in action between the &alpha-and
&beta-racemates is not so pronounced ([16] ). Gross et al. ([17] ) investigated alpha-and betaprodine in man, and Houde et al. ([18]
) reported that alphaprodine had a weaker analgesic action than
morphine and showed side effects in 10% of the patients. The use of
alphaprodine as a postoperative analgesic has been investigated by
Bachrach et al. ([15] ). Evidence that these substances show addiction properties has been obtained by Isbell ([19] ). Janssen ([20]
) has recently determined the analgesic activity of prodine isomers
prepared in our own laboratories and obtained the following results,
morphine hydrochloride being taken as 100; in mice, &alpha-form
racemate 200, &beta-form racemate 835, in rats, &alpha-form
racemate 190, &beta-form racemate 3000.
Randall & Lehmann ([14] ) reported that the activity of 3-ethyl-1 -methyl-4-phenyl-4-propionoxypiperidine (XVI, R = C 2H 5)
(no information concerning isomers is given) was 6.4 times that of
morphine while the corresponding acetoxy ester possessed only half the
latter's activity. Thus in analgesics of formula (XVI), activity
increases in the order (XVI, R = H), (XVI, R = CH 3) and (XVI, R = C 2H 5) - i.e., with increasing size of the 3-substituent. McElvain ([21] ) has synthesized and tested the next higher member (XVI,R = n-C 3H 7)
which is stated to have profound activity in rats at doses of 8 mg/kg,
but no direct comparison has been made with the lower homologues and it
is therefore not possible to draw any conclusions with regard to the
optimal size of the 3-substituent from this evidence. Large groups in
the 3-position such as benzyl completely abolish activity ([21] ) (see compounds 8-10, 14 and 15, table 2). The acetoxy and butyroxy esters of 1-methyl-3- n-propyl-4-phenylpiperidin-
1-ol are less active than the propionoxy ester, the latter again
representing the most active member of a series.
Inclusion of a double bond into the 3-substituent of XVI results in
a highly active compound. This has been shown by the recent report of
the analgesic activity of the 3-allyl analogue of prodine - i.e.,
3-allyl-l-methyl-4-phenyl-4-propionoxypiperidine (XVI, R = CH 2CH = CH 2). Benson et al. ([69]
) have found that this compound is approximately ten times as active as
alphaprodine with no corresponding increase in its toxicity [details of
synthesis have become available subsequent to the submission of this
paper for publication ([73)] ].
May ([70]
) has reported structural isomers of alpha- and betaprodine in which
the 3-methyl and 4-propionoxy substituents are interchanged. These
analogues possess very little analgesic activity.
From information so far available, it appears that the 4-aryl
substituent of prodine-type compounds must be a phenyl group if optimum
activity is to be attained. In the case of alphaprodine, Randall and
Lehman ([14]
) have reported substitution of 4-phenyl by 4-cyclohexyl to result in a
considerable fall in activity (see compound 5, table 2), while work in
our own laboratories ([30] ) has shown that replacement by p-tolyl, o-tolyl and m-tolyl gives progressively less active substances (see compounds 25, 18 and 22, table 2).
The
key intermediates in the synthesis of compounds of type (XVI) are
3-substituted 4-piperidones (XVII); reaction of the ketone (XVII)with
an aryl lithium and subsequent acylation of the resultant tertiary
alcohol (XVIII) gives the "reversed ester" (XVI). The 3-methyl
substituted compounds listed in table 2 were prepared from 1:
3-dimethyl-4-piperidone (XVII, R = CH 3); Howton's preparation of this ketone, a modification of the usual 4-piperidone synthesis ([22] ), is outlined in flow sheet 3.
Table 2
Flow Sheet 3
This
method cannot serve as a general procedure for the preparation of
higher 3-alkylhomologues as the necessary substituted acrylic esters
are not readily available. Treatment of
3-carbethoxy-l-methyl-4-piperidone (XIX) with an alkyl halide leads, as
shown by McElvain ([23]
) and confirmed in or own laboratories, to an N- rather than a
C-alkylated product. C-alkylation is possible once the basic nature of
the nitrogen atom of the 4-piperidone is masked; thus McElvain ([23]
) has C-alkylated 1-benzoyl-3-carbethoxy-4-piperidone. The ketone (XIX)
has been successfully C-allylated and benzylated by treatment with
allyl and benzyldimethylanilinium bromide respectively ([21] ). Decarboxylation (prior reduction of allyl to propyl is necessary) of the products leads to the 3- n-propyl and 3-benzyl ketones (XVII, R = n-C 3H 7 and -CH 2C 6H 5 respectively), from which compounds 8-13 in table 2 were prepared.
Recently, a new one-stage synthesis of the parent alcohol of the reversed ester of pethidine has been reported ([25]
). The method involves the amino-methylation of
&alpha-methylstyrene by means of a methylamine
hydrochloride-formalin mixture and gives the 4-piperidinol (XX) in 30%
yield together with a substituted oxazine (XXI) as the major product. A
modification of the method, employing N, N', N"
-trimethyltrimethylenetriamine gives the reversed ester itself in 30%
yield ([26] ); use of higher &alpha-substituted styrenes leads to prodine and its analogues ([67] ).
Treatment of the 4-piperidone (XVII) with phenyl lithium may give rise to two isomeric tertiary alcohols in which the C 6H 5 and R groups are respectively cis (XXII) and trans (XXIII). In the case of 1: 3-dimethyl-4-piperidone (XVII, R=CH 3), Ziering & Lee ([29]
) isolated two isomers by fractional crystallization of the propionic
ester hydrochlorides. They named the two isomers alpha- and betaprodine
respectively and assigned the cis (CH 3/C 6H 5) configuration to the alpha- and the trans(CH 3/C 6H 5)
to the beta-compound. These assignments were not rigidly established
and were stated to be based upon the easier break-down of the
alpha-isomer under hydrolytic conditions and upon the pharmacological
results, presuming the more active beta-isomer to be more closely
related to the potent analgesic-dihydrodeoxy-morphine -D than the
alpha-isomer as shown on the left ([14] ).
Conventional
line representations, as above, may give a false indication of actual
molecular shape; this can be derived with greater reliability by the
aid of molecular models. To construct these, it is necessary to
consider the possible conformations of the piperidine ring
substituents. Application of the principles of conformational analysis
leads to (XXIV) and (XXV) as the most probable conformations of the cis and trans
isomers respectively (see Fig. 1). Comparison of these models with that
of morphine (XXVI) (see Fig. 1) and a consideration of" fit" at a
proposed receptor surface first led the present authors to question
Ziering & Lee's configurational assignments ([27] ). Of the two isomers, the three-dimensional arrangement (XXIV, cis CH 3/C 6H 5)
bears the greater resemblance to morphine and would therefore be
expected to represent the more analgesically active isomer
(betaprodine), while the less active isomer (alphaprodine) is
represented by (XXV, trans CH 3/C 6H 5).
Support for the reversal of the original
configurational assignments is provided by hydrolysis studies on alpha-
and betaprodine. The rate of hydrolysis of betaprodine has been shown
to be greater than that of the alpha-compound ([28]
); the former must therefore have an equatorial (as in XXIV) and the
latter compound an axial propionoxy group (as in XXV). Consideration of
the isomer ratios obtained experimentally leads to the same conclusion
- the original workers ([29] ) obtained an alpha : betaprodine ratio of 1.4:1, and Beckett et al. ([30]
) obtained 3: 1. The stereochemistry of addition of lithium aryls to
the piperidone (XXVII) favours approach of the aryl group from the
least hindered side of the molecule - i.e., attack from side ( b) wilt be preferred to attack from side ( a)
(see XXVII), and in the product, the predominating isomer will have an
equatorial aryl group. If these arguments are correct, increase in size
of the aryl addendum should favour attack from side ( b) to an even greater degree. Our own results bear out this contention; treatment of the ketone (XXVII) with m- or p-tolyl lithium gives isomeric pairs of compounds in which one isomer predominates, whereas addition of the highly hindered o-tolyl or o-methoxyphenyl
lithium results in the formation of one isomer exclusively. Evidence
for the configurational identity of the isomers formed in major amount
in the addition of phenyl lithium and m- and p-tolyl lithium to the piperidone (XXVII) and the single isomers formed upon addition of o-tolyl and o-methoxyphenyl
lithium to this ketone, is provided by infra-red absorption
measurements. The latter reveal a consistency of pattern for these
isomers in the regions 990 to 1,020 cm-1, 1,350 to 1,385 cm-1 and 2,670
to 2,780 cm-1, which is completely different from that shown by isomers
formed in minor amount upon addition of phenyl lithium and m- and p-tolyl lithium to the piperidone (XXVII). This evidence is presented in greater detail in a recent paper ([30] ).
FIGURE 1 - Diagrammatical representation of the
three-dimensional arrangement of analgesics and the "analgesic receptor
surface".
The
diagrams represent the lower surfaces of the drug and the upper surface
of the receptor- i.e., complementary surfaces. In front of, behind, and
in the plane of the paper are represented by 0,........, and _______
respectively.
Glassman & Seifter ([31]
) have recently described the analgesic activity of a series of
azacycloheptanes (hexamethyleneimines) related to pethidine. They
found, in general, that replacement of the six-membered ring of
pethidine and related compounds by a seven-membered one results in at
least a 50% loss in analgesic potency. The straight pethidine analogue
(XXVIII, compound I, table 3) is about one-third as active as
pethidine; various modifications of the 4-phenylaza-cycloheptane
molecule gave a number of compounds with analgesic potency equivalent
to or better than that of pethidine. Changes in potency as a result of
such modifications appear to parallel similar changes in the pethidine
molecule itself. The most active compounds in this series were obtained
by substitution of a methyl group in the 2 or 3 position of the ring
(e.g., compounds 2, 3 and 7, table 3); substitution in the 5, 6 or 7
positions gave compounds with little or no activity (e.g., compounds 4,
5 and 6, table 3). Reversal of the carbethoxy group coupled with
3-methyl substitution gave the prodine analogue (compound 18, table 3).
The latter was the most active member of the series being approximately
ten times as active as pethidine; its configuration is provisionally
reported as cis(CH 3/C 6H 5) ([32] ). Ketobemidone (1 - methyl - 4 - m
- hydroxyphenyl - 4 - propionylpiperidine) is stated to be
approximately thirty times as active as pethidine; the analogue in this
series (compound 22, table 3) shows only a twofold increase over the
pethidine analogue (compound 1, table 3). Although the latter is less
active an analgesic than some of the other members of this series, its
clinical use has been studied in detail as it appears to be without
certain of the undesirable side-effects of morphine and pethidine ([33] , [33] and [35] ). Fraser ([71]
) reports that the addictive potentialities of the pethidine analogue
and certain 1: 2 - and 1: 3-dimethyl derivatives (compounds 1, 3 and 7,
table 3) are either low or non-existent, while the alphaprodine
analogue (compound 18, table 3) has addiction liability equal to that
of pethidine and approaching that of morphine.
Synthesis of 4-cyano-l-methyl-4-phenylazacycloheptane (XXIX) by
condensation of the amine (XXX) with phenyl-acetonitrile - i.e., by a
method analogous to the synthesis of pethidine cyanide, gave only a
small yield of the desired product. Flow sheet 4 outlines the reactions
finally employed by Diamond ([32] , [68]
) for the preparation of the cyanide (XXIX) and its conversion into the
pethidine analogue (XXVIII) and the ketone (XXXI). A similar synthesis
has been reported by Blicke & Tsao ([36] ).
Flow sheet 4
>The
pethidine analogue (XXVIII) has been resolved via the menthyl ester
diastereoisomers and also by crystallization of the (+)-acid tartrates.
Diamond ([32]
) states that preliminary reports indicate that most of the analgesic
activity of the racemic mixture may reside in one of the isomers.
Modifications of the above synthesis employing m-methoxyphenylace-tonitrile
and 2'-thienylacetonitrile gave the ketobemidone analogue (XXXII,
compound 22, table 3) and 4-(2'-thienyl)-4 -carbethoxy- 1 -
methylazacycloheptane (XXXIII, compound 23, table 3) respectively.
Condensation
of 1 - dimethylamino- 2- chloropropane (XXXIV) with phenylacetonitrile
yields a mixture of two isomeric cyanides (XXXV and XXXVI) probably
owing to the intermediate formation of an ethyleneiminium salt (XXXVII)
[c.f. the synthesis of methadone and isomethadone cyanides ([37] )].
Application
of the general synthesis (see flow sheet 4) to these two cyanides leads
to the 1-2 dimethyl compounds (XXXVIII, XXXIX and XL, compounds 2, 7
and 13, table 3) and to the 1-3 dimethyl compound (XLI, compound 3,
table 3); complications in the synthesis arise on account of the
existence of diastereoisomeric forms. The 1-5 and 1-7 dimethyl
compounds (XLII and XLIII, compounds 4 and 6, table 3) were obtained by
condensation of the cyanide (XLIV) with crotonaldehyde and methyl vinyl
ketone respectively. The products, after reduction to the alcohols,
were treated with thionyl chloride to give the chlorocompounds (XLV and
XLVI); the latter were used in the general synthesis as before.
TABLE 3
Analgesic activities of Azacycloheptanes
Compound No. | R | R' | Ring substituents | Relative analgesic activitya (pethidine = 1) |
1 | C 6H 5
| CO 2C 2H 5
| -
| 0.3 |
2 | "
| "
| 2-CH 3
| 0.9 |
3 | "
| "
| 3-CH 3
| 2.3 |
4 | "
| "
| 5-CH 3
| <0.3
|
5 | "
| "
| 6 -CH 3
| Almost none
|
6 | "
| "
| 7-CH 3
| <0.2
|
7 | "
| CO 2CH 3
| 2-CH 3
| 1.1 |
8 | ''
| CO 2C 3H 7n
| ''
| 0.3 |
9 | "
| CO 2CH (CH 3) 2
| ''
| 1.1 to 0.3
|
10 | "
| CO 2(CH 2) 2N(C 2H 5) 2
| -
| 0.3 |
11 | "
| COC 2H 5
| -
| <0.2
|
12 | "
| COC 3H 7n
| -
| <0.2
|
13 | "
| COC 2H 5
| 2-CH 3
| 0.6 |
14 | "
| SO 2C 2H 5
| -
| 0.3 |
15 | "
| OCOCH 3
| 2-CH 3
| <0.3
|
16 | "
| "
| 3-CH 3
| 0.2 |
17 | "
| OCOC 2H 5
| 2-CH 3
| 0.6 |
18 | "
| "
| 3-CH 3
| 10 |
19 | "
| H
| -
| None
|
20 | "
| "
| 2-CH 3
| <0.3
|
21 | "
| "
| 3-CH 3
| <0.3
|
22 | m-OH.C6H4
| COC 2H 5
| -
| 0.7 |
23 | 2'-thienyl
| CO 2C 2H 5
| -
| None
|
a Measured in rats by intraperitoneal injection.
Flow sheet 5 outlines the reactions employed by Diamond ([32]
) for the synthesis of analogues of the reversed esters of pethidine.
One method involves cyclization of the dicyanide (XLVII) by means of
lithium ethylanilide (Ziegler's method) and the other two, replacement
of the cyanide group of the precursor (XXIX) by the hydroxy or
carbomethoxy group. These transformations were carried out in two ways:
Hofmann degradation of the derived amide (XLVIII) to the amine (XLIX)
followed by treatment with nitrous acid gave the tertiary alcohol (L);
cleavage of the cyanide group with sodamide gave the hydrocarbon (LI),
which on oxidation with lead tetraacetate gave the 4-carbomethoxy
compound (LII). Application of the latter method to the cyanides (XXXV
and XXXVI) gave compounds 15 and 16 in table 3. The cyanoester (LIII),
obtained by condensation of the secondary amine (LIV) with
&gamma-chloro- n-propylcyanide, underwent a Dieckmann
condensation on treatment with sodium methoxide; the resultant mixture
(LV and LVI), on heating with hydrochloric acid, gave
1:3-dimethyl-4-azacycloheptanone (LVII), from which was derived the
prodine analogue (LVIII, compound 18, table 3; see flow sheet 6). The
latter compound is believed to be one pure diastereoisomeric form (the
other isomer has not been isolated); its configuration is pro
visionally reported as cis (CH 3/C 6H 5) on the basis of pyrolysis studies.[3]
Flow sheet 5
Flow sheet 6
Nazarov has reported the synthesis of a series of 4-piperidinol
esters derived from 1-alkyl-2 : 5-dimethyl-4-piperidone (LIX). Ketones
of this type are obtained from technically available
dimethylvinylethinylcarbinol (LX) as indicated in flow sheet 7 ([38] ).
Flow sheet 7
The ketone (LIX) may exist in cis and trans
forms, but attempts at isomer separation in the case of (LIX, R = H)
have yielded only one form (probably the trans isomer) (39). Promedol,
1 : 2: 5-trimethyl-4-phenyl-4-propionoxypiperi-dine (LXI, R = CH 3, R' = C 2H 5)
is one of the isomers obtained by treatment of the ketone (LIX, R =
CH3) with phenyl lithium and acylation of the resultant tertiary
alcohols ([40] ). The analgesic activity of promedol is reported to be several times greater than that of pethidine ([41] , [42] ). Further details of the stereochemistry of esters of 1: 2: 5-tri-methyl-4-phenylpiperidinol have recently been published ([43]
); a stereoisomer, isopromedol, is reported to be 2 to 3 times more
active than promedol and has been approved for clinical use in the USSR
([44] ). Further details concerning promedol have been given in a recent paper in this bulletin ([72] ).
It has been suggested that the activity of pethidine-type analgesics
lies in the fact that the 4-phenylpiperidine ring system represents an
essential fragment of the morphine nucleus and that the
three-dimensional structure of the latter is simulated more or less
closely by the various active compounds ([45] ). The azacycloheptanes of Diamond ([32]
) may similarly be considered as morphine fragments (see formulae LXII
and LXIII). Recent workers have placed less emphasis upon the need for
the piperidine ring as such and have stressed the importance of
over-all spatial configuration ([46] , [47] ).
The decisive role of stereochemical factors in analgesic action is demonstrated by ([1] ) the many examples of enantiomorphic pairs in which most of the activity resides in one of the isomers; ([2] ) the considerable differences in activity amongst the prodine isomers; and ([3] ) the relationships between analgesics and their antagonists- thus morphine and nalor- phine [N-allyl normorphine]
have identical configurations; levorphan, a potent analgesic, is
antagonized by (-)-3-hydroxy -N-allylmorphinan of identical
configuration, but not by the (+)-allyl, compound possessing the same
configuration as the almost inactive dextrorphan ([27]
). The present authors have obtained further evidence for the
configurational requirements of analgesics by relating the
configuration of a number of the more analgesically active isomers of
enantio-morphic pairs to D-(-)-alanine ([48] , [49] and [50]
). From this evidence they postulated that, for an organic compound to
exhibit high analgesic activity, the following essential features are
necessary:
A basic centre which is partially ionized as a cation at
physiological pH, in order that it may be able to associate with an
anionic site in the receptor surface. A proportion of unionized
molecules is probably necessary to facilitate penetration of cell
membranes.
A flat aromatic structure in the molecule to allow of a strong
collective van der Waals' force bonding to a flat portion of the
receptor reinforcing the ionic bond mentioned in ([1] ), which otherwise would not be sufficiently permanent, because of ion exchange under biological conditions.
The basic group and the flat structure to be almost in the same
plane; this to be accomplished by a completely rigid molecule or a
slightly less rigid one held in the correct configuration by steric or
other constraints.
A suitably positioned projecting hydrocarbon moiety to form,
with the basic centre and the flat aromatic structure, a
three-dimensional geometric pattern indicated in figure 1 ([27] ).
Active analgesics were shown to have structures which enable them to
present similar surfaces to allow of their association with a proposed
"analgesic receptor surface" (see Fig. 1).
Both pethidine (pKa' 8.72) ([51] ) and alphaprodine (pKa' 8.73) ([51] ) satisfy requirement ([1]
) in that they are substantially ionized as cations at physiological
pH, and in both, the 4-phenyl substituent represents the necessary flat
aromatic structure. Evidence of stereospecificity derived from study of
analgesic antagonists is abundantly available in the case of
pethidine-type compounds (references 52--59 relate to antagonism of
pethidine by nalorphine, 54 and 55 to alpha-prodine by nalorphine, and
60 to alphaprodine by (-)-3-hydroxy-N-propargylmorphinan). Pethidine
probably exists as an equilibrium mixture of the two conformational
arrangements .(LXIV) and (LXV), the equatorial-phenyl form
predominating owing to its greater thermodynamic stability (see fig.
1). Models reveal that both forms are capable of fitting the proposed
receptor surface, although (LXIV) would be expected to fit more closely
than (LXV), owing to its greater resemblance to the rigid morphine
structure (XXVI). As the energy difference between the two forms is
likely to be small, it is possible that the stability imparted upon
absorption at the site, greatest in the case of the axial phenyl
conformation, may override the non-bonded interaction factors in
molecule itself in determining the conformation of pethidine at the
site of action (similar arguments apply to the reversed esters of
pethidine).
The most probable conformations of alpha- and betaprodine have
already been discussed (see "Stereochemistry" on p. 44). Models show
that both isomers can fit the proposed receptor site, but of the two
forms, the cis (Me/Ph) should fit better than the trans (Me/Ph) isomer.
It is possible to explain the increase in activity of compounds
obtained by the substitution of a 3-alkyl group into the reversed ester
of pethidine in terms of a more bulky hydrocarbon moiety improving the
fit in the cavity of the receptor site.
In a recent paper, Beckett, Casy & Harper ([61]
) have advanced the hypothesis that oxidative dealkylation to produce
nor-compounds at the "analgesic receptor site" is the first step in the
reaction sequence leading to analgesia. The influence of the basic
group upon analgesic activity may thus be considered from two aspects
-- (1) the steric requirements of the anionic receptor site, and ([2]
) the ease of dealkylation. The activity of a series of methadone- and
thiambutene-type analgesics has been shown to decrease upon increase in
the "effective width" of the basic group, and from this evidence the
anionic site of the receptor surface has been assigned certain
dimensions ([62] ).
The high activity of certain N-substituted norpethidine compounds
must now be considered in the light of these facts. Evidence that the
phenyl and benzyl groups are too large to fit at the anionic site is
provided by the absence of activity in norpethidine-type compounds
bearing these sub-stituents upon the nitrogen atom (1, 66). Increase of
the chain length giving the N-phenylethyl compound results in an
increase in activity over that of the parent compound. The steric
limitations of the anionic site must therefore be less restricted
farther removed linearly from the focus of charge, and may allow of
additional van der Waals&rsquo force bonding between the aromatic
ring at the end of the chain and the receptor site. The high activity
of &beta-morpholinoethyl norpethidine and its sulphur analogue may
be explained in a similar way, additional bonding being provided in
these cases by the lone-pair electrons on the oxygen and sulphur atoms
respectively (cf. the increased activity of the morpholino analogue of
methadone over its parent compound ([63]
)). The effect of chain branching upon activity may also be interpreted
in terms of steric limitations at the anionic site. Branching at the
carbon atom &alpha- to the piperidine ring nitrogen atom results in
a greater reduction in activity than does branching at the
&beta-carbon atom, where steric limitations are not so great. In
addition to these steric factors it is also necessary to stress that
the presence of electrical dipoles in the &beta-phenylethyl chain,
etc., may result in an increase in the rate of dealkylation over that
of pethidine leading to a consequent increase in activity.
We wish to thank Wyeth Laboratories for making available information
concerning the azacycloheptanes. We also thank the editor of the Journal of Pharmacy and Pharmacology for making available copies from which certain diagrams in the text were prepared.
1 4-carbethoxy-l-methyl-4-phenylpiperidine, also known as Meperidine and Dolantin.
2 The corresponding N-tosyl compounds are also employed, conversion to the nor-compound (X) being carried out in this case by hydrolysis with sulphuric acid. ([24] )
3 If this isomer proves to be the one formed in major amount, it would be expected to have the trans (CH 3/C 6H 5) configuration from a consideration of the stereochemistry of addition to cyclic ketones (30).
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