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Biological activity of apomorphine fragments: Dissociation of emetic and stereotypical effects
Neurophormacology.
1973, 12,83-85
PergamonPress. Printedin Cit.Britain.
PRELIMINARY NOTE
BIOLOGICAL DISSOCIATION
ACTIVITY OF APOMORPHINE FRAGMENTS : OF EMETIC AND STEREOTYPICAL EFFECTS A. M. BURKMAN
Division of Pharmacology,
College of Pharmacy, The Ohio State University, Columbus, Ohio (Accepted
28 July 1972)
Summary-2-Amino-5,6-dihydroxy-l,2,3,4-tetrahydronaphthalene, 2-methylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene and 2-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene were all found to be potent emetics in dogs; potency increasing with additional N-Substitution. The methyl and dimethyl derivatives were more active than the reference standard apomorphine. On the other hand, the compounds did not provoke compulsive behavioral activities in either mice or pigeons, a fact which disrupts the pattern of parallelism that had previously been established.
The ability of apomorphine to produce stereotyped behavior in rodents (characterized by compulsive gnawing and chewing movements) has long been recognized (HARNACK, 1874). It is only in recent years, however, that attempts were made to identify the anatomical and biochemical locus of this central excitatory action (ERNST and SMELIK, 1966; ERNST, 1967; AND~N, RUBENSON, FUXE and HOKFELT, 1967). Although much of the evidence is circumstantial, the effect is presumed to originate as a result of apomorphine’s ability to directly stimulate dopaminergic receptors in the corpus striatum. Apomorphine is also capable of provoking a functionally equivalent type of compulsive behavior in pigeons marked by continuous, forceful, repetitive pecking (AMSLER, 1923). The origin of this drug-induced avian stereotypy and its relationship to the rodent response has never been clearly defined although KOCH, CANNON and BURKMAN (1968) in their studies of norapomorphine derivatives observed a striking parallelism in the gnawing and pecking potencies of their homologous compounds. A third and more familiar action of apomorphine is the emesis it generates in a variety of animal taxa. In their experiments with apomorphine derivatives HENSIAK, CANNON and BURKMAN (1965), KOCH et al. (1968), SPRENGER, CANNON, BARMAN and BLJRKMAN(1969), CANNON et al. (1972) and BURKMAN and CANNON (1972) all consistently demonstrated a positive correlation between the ability of these substances to trigger emesis in dogs and both murine and avian stereotypy. Although different anatomical sites may be involved in the initiation of each of these responses the quantitative parallelism in potencies among the substances suggests that the biochemical substrates for these three activities may be similar. Indeed, the work of F~~RSTERand GR~~BNER(1966) supports the idea that the emetic actions of apomorphine may involve activation of an adrenergic system (presumably in the Area postrema). There has never been ample evidence to establish this notion as fact but it seems reasonable that if such a hypothesis is to have substance the pattern of parallelism should remain intact, at least for apomorphine-like substances that have access to the central 83
84
A. M.
&JRKMAN
nervous system. Our experiments with several tetrahydronaphthalene derivatives, which can be considered to be fragments of the apomorphine molecule, has uncovered, for the first time, a dissociation of emetic and stereotypical activities. METHODS
The compounds were screened for several apomorphine-related activities, viz., emesis in dogs (mongrel, both sexes), compulsive pecking in pigeons (domestic, both sexes), and compulsive gnawing in mice (Harlan ICR, female). In addition, indices of gross acute toxicity expressed in terms of convulsions and lethality were also estimated. Drugs were administered as either hydrobromide or hydrochloride salts in isotonic saline solutions i.m. (dogs and pigeons) and i.p. (mice). The method for assessing emetic activity has been described elsewhere (KOCH et al., 1968) and involves comparison of the threshold emetic dose (TED) of a compound with the TED of apomorphine reference standards in the same animals. Compounds that do not provoke emesis in doses 100 times the apomorphine TED are judged to be inactive. Cumulative pecking responses in birds were recorded with an electromechanical monitor (BURKMAN, 1970) and gnawing activity in mice was evaluated as a dose-related quanta1 response. RESULTS
AND
DISCUSSION
The comparative lethal and emetic properties of the three tetrahydronaphthalene derivatives are presented in Table 1. All compounds are potent emetics. Indeed, the secondary and tertiary aminonaphthalenes are more potent than the parent apomorphine. In concentrations slightly above the TED these compounds begin to exhibit a dose-dependent Table 1. Biological activities of apomorphine
and several tetrahydronaphthalene
fragments in mice and dogs
Tetrahydronaphthalene
Apomorphine
derivatives
Lethality in mice
Emesis in dogs TED ratio:
R.P.
Compound
R
R’
LD50*
R.P.t
Apomorphine 2-AminoDTHN § 2-MethylaminoDTHN
H H
H CH,
559+23 1346+77 1386&73
1.00 0.42 0.41
0~08/0~08 0.0710.48 0~08/0~06
1 .oo 0.17 1.20
CH,
CH,
277119
2.02
0.08/0.05
1.60
2-DimethylaminoDTHN
*Median Lethal Dose i S.E., in pmoles of base/kg body weight, i.p. tRelative potency. :Ratio of the Threshold Emetic Dose (pmoles of base/kg, i.m.) for apomorphine compound; 4 dogs per drug. §DTHN = 5,6-dihydroxy-1,2,3,4_tetrahydronaphthalene.
to the TED for the test
Pharmacology
of apomorphine
fragments
85
depression. Dogs become increasingly ataxic and lethargic. At doses 10 times the TED the dogs become prostrate (conscious but immobile). There is no ptosis evident and the animals are capable of aversive motor response if stimulated. More significant is the fact that these substances do not provoke pecking in pigeons and only the most tentative and trivial gnawing in mice. They exhibit no convulsant activity in mice (which is characteristic of apomorphine) although sympathomimetic symptoms such as piloerection and tachycardia are prominent. The dissociation of emetic and compulsive behavioral effects implies that there may be different molecular requirements for each of these activities although, clearly, this is not the only valid interpretation. Differences in regional distribution among structurally related compounds may make one site (e.g. the corpus striatum) less accessible than another (e.g. the chemoreceptor trigger zone). Until information relative to these factors becomes available, explanations remain conjectural. Acknowledgement-The University of Iowa.
three tetrahydronaphthalene
derivatives
were supplied
by Dr. J. G.
CANNON,
REFERENCES AMSLER,C. (1923). Beitrage zur Pharmakologie des Gehirns. Archs exp. Path. Pharmak. 97: 1-14. AND&N,N.-E., RUBENSON,A., FUXE, K. and HOKFELT,T. (1967). Evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmac. 19: 627-629. BURKMAN,A. M. (1970). Automatic monitoring of apomorphine-induced pecking in pigeons. J. exp. Anal. Behav. 13: 349-350. BURKMAN,A. M. and CANNON, J. G. (1972). Screening nornuciferine derivatives for apomorphine-like activity. J. Pharmaceut. Sci. 61: 813-814. CANNON,J. G., SMITH,R. V., MODIRI, A., SOOD,S. P., BORGMAN,R. J., ALEEM,M. A. and LONG, J. P. (1972). Centrally Acting Emetics, V. Preparation and pharmacology of IO-hydroxy-11-methoxyaporphine (isoapocodeine). J. med. Chem. 15: 273-276. ERNST,A. M. (1967). Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacologia 10: 316326. ERNST,A. M. and SMELIK,P. G. (1966). Site of action of dopamine and apomorphine on compulsive gnawing behavior in rats. Experientiu 22: 837-838. FiiRSrs~, W. und GRKBNER, S. (1966). Einfluss von Dopamin und MAO-Hemmstoffen auf zentral ausgelijstes Erbrechen. Acta biol. med. germ. 16: 650-657. HARNACK, E. (1874). Ueber die Wirkungen des Apomorphins am Saugethier und am Frosch. Archs exp. Path. Pharmak.
2: 254-306.
HENSIAK,J. F., CANNON,J. G. and BURKMAN,A. M. (1965). N-allylnorapormorphine.
J. med. Chem. 8:
557-559.
KOCH, M. V., CANNON,J. G. and BURKMAN,A. M. (1968). Centrally Acting Emetics, II. Norapomorphine and derivatives, J. med. Chem. 11: 977-981. SPRENGER,W. K., CANNON,J. G., BARMAN,B. K. and BURKMAN,A. M. (1969). Centrally Acting Emetics, III. Derivatives of p-naphthylamine, J. med. Chem. 12: 487490.
1973, 12,83-85
PergamonPress. Printedin Cit.Britain.
PRELIMINARY NOTE
BIOLOGICAL DISSOCIATION
ACTIVITY OF APOMORPHINE FRAGMENTS : OF EMETIC AND STEREOTYPICAL EFFECTS A. M. BURKMAN
Division of Pharmacology,
College of Pharmacy, The Ohio State University, Columbus, Ohio (Accepted
28 July 1972)
Summary-2-Amino-5,6-dihydroxy-l,2,3,4-tetrahydronaphthalene, 2-methylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene and 2-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene were all found to be potent emetics in dogs; potency increasing with additional N-Substitution. The methyl and dimethyl derivatives were more active than the reference standard apomorphine. On the other hand, the compounds did not provoke compulsive behavioral activities in either mice or pigeons, a fact which disrupts the pattern of parallelism that had previously been established.
The ability of apomorphine to produce stereotyped behavior in rodents (characterized by compulsive gnawing and chewing movements) has long been recognized (HARNACK, 1874). It is only in recent years, however, that attempts were made to identify the anatomical and biochemical locus of this central excitatory action (ERNST and SMELIK, 1966; ERNST, 1967; AND~N, RUBENSON, FUXE and HOKFELT, 1967). Although much of the evidence is circumstantial, the effect is presumed to originate as a result of apomorphine’s ability to directly stimulate dopaminergic receptors in the corpus striatum. Apomorphine is also capable of provoking a functionally equivalent type of compulsive behavior in pigeons marked by continuous, forceful, repetitive pecking (AMSLER, 1923). The origin of this drug-induced avian stereotypy and its relationship to the rodent response has never been clearly defined although KOCH, CANNON and BURKMAN (1968) in their studies of norapomorphine derivatives observed a striking parallelism in the gnawing and pecking potencies of their homologous compounds. A third and more familiar action of apomorphine is the emesis it generates in a variety of animal taxa. In their experiments with apomorphine derivatives HENSIAK, CANNON and BURKMAN (1965), KOCH et al. (1968), SPRENGER, CANNON, BARMAN and BLJRKMAN(1969), CANNON et al. (1972) and BURKMAN and CANNON (1972) all consistently demonstrated a positive correlation between the ability of these substances to trigger emesis in dogs and both murine and avian stereotypy. Although different anatomical sites may be involved in the initiation of each of these responses the quantitative parallelism in potencies among the substances suggests that the biochemical substrates for these three activities may be similar. Indeed, the work of F~~RSTERand GR~~BNER(1966) supports the idea that the emetic actions of apomorphine may involve activation of an adrenergic system (presumably in the Area postrema). There has never been ample evidence to establish this notion as fact but it seems reasonable that if such a hypothesis is to have substance the pattern of parallelism should remain intact, at least for apomorphine-like substances that have access to the central 83
84
A. M.
&JRKMAN
nervous system. Our experiments with several tetrahydronaphthalene derivatives, which can be considered to be fragments of the apomorphine molecule, has uncovered, for the first time, a dissociation of emetic and stereotypical activities. METHODS
The compounds were screened for several apomorphine-related activities, viz., emesis in dogs (mongrel, both sexes), compulsive pecking in pigeons (domestic, both sexes), and compulsive gnawing in mice (Harlan ICR, female). In addition, indices of gross acute toxicity expressed in terms of convulsions and lethality were also estimated. Drugs were administered as either hydrobromide or hydrochloride salts in isotonic saline solutions i.m. (dogs and pigeons) and i.p. (mice). The method for assessing emetic activity has been described elsewhere (KOCH et al., 1968) and involves comparison of the threshold emetic dose (TED) of a compound with the TED of apomorphine reference standards in the same animals. Compounds that do not provoke emesis in doses 100 times the apomorphine TED are judged to be inactive. Cumulative pecking responses in birds were recorded with an electromechanical monitor (BURKMAN, 1970) and gnawing activity in mice was evaluated as a dose-related quanta1 response. RESULTS
AND
DISCUSSION
The comparative lethal and emetic properties of the three tetrahydronaphthalene derivatives are presented in Table 1. All compounds are potent emetics. Indeed, the secondary and tertiary aminonaphthalenes are more potent than the parent apomorphine. In concentrations slightly above the TED these compounds begin to exhibit a dose-dependent Table 1. Biological activities of apomorphine
and several tetrahydronaphthalene
fragments in mice and dogs
Tetrahydronaphthalene
Apomorphine
derivatives
Lethality in mice
Emesis in dogs TED ratio:
R.P.
Compound
R
R’
LD50*
R.P.t
Apomorphine 2-AminoDTHN § 2-MethylaminoDTHN
H H
H CH,
559+23 1346+77 1386&73
1.00 0.42 0.41
0~08/0~08 0.0710.48 0~08/0~06
1 .oo 0.17 1.20
CH,
CH,
277119
2.02
0.08/0.05
1.60
2-DimethylaminoDTHN
*Median Lethal Dose i S.E., in pmoles of base/kg body weight, i.p. tRelative potency. :Ratio of the Threshold Emetic Dose (pmoles of base/kg, i.m.) for apomorphine compound; 4 dogs per drug. §DTHN = 5,6-dihydroxy-1,2,3,4_tetrahydronaphthalene.
to the TED for the test
Pharmacology
of apomorphine
fragments
85
depression. Dogs become increasingly ataxic and lethargic. At doses 10 times the TED the dogs become prostrate (conscious but immobile). There is no ptosis evident and the animals are capable of aversive motor response if stimulated. More significant is the fact that these substances do not provoke pecking in pigeons and only the most tentative and trivial gnawing in mice. They exhibit no convulsant activity in mice (which is characteristic of apomorphine) although sympathomimetic symptoms such as piloerection and tachycardia are prominent. The dissociation of emetic and compulsive behavioral effects implies that there may be different molecular requirements for each of these activities although, clearly, this is not the only valid interpretation. Differences in regional distribution among structurally related compounds may make one site (e.g. the corpus striatum) less accessible than another (e.g. the chemoreceptor trigger zone). Until information relative to these factors becomes available, explanations remain conjectural. Acknowledgement-The University of Iowa.
three tetrahydronaphthalene
derivatives
were supplied
by Dr. J. G.
CANNON,
REFERENCES AMSLER,C. (1923). Beitrage zur Pharmakologie des Gehirns. Archs exp. Path. Pharmak. 97: 1-14. AND&N,N.-E., RUBENSON,A., FUXE, K. and HOKFELT,T. (1967). Evidence for dopamine receptor stimulation by apomorphine. J. Pharm. Pharmac. 19: 627-629. BURKMAN,A. M. (1970). Automatic monitoring of apomorphine-induced pecking in pigeons. J. exp. Anal. Behav. 13: 349-350. BURKMAN,A. M. and CANNON, J. G. (1972). Screening nornuciferine derivatives for apomorphine-like activity. J. Pharmaceut. Sci. 61: 813-814. CANNON,J. G., SMITH,R. V., MODIRI, A., SOOD,S. P., BORGMAN,R. J., ALEEM,M. A. and LONG, J. P. (1972). Centrally Acting Emetics, V. Preparation and pharmacology of IO-hydroxy-11-methoxyaporphine (isoapocodeine). J. med. Chem. 15: 273-276. ERNST,A. M. (1967). Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacologia 10: 316326. ERNST,A. M. and SMELIK,P. G. (1966). Site of action of dopamine and apomorphine on compulsive gnawing behavior in rats. Experientiu 22: 837-838. FiiRSrs~, W. und GRKBNER, S. (1966). Einfluss von Dopamin und MAO-Hemmstoffen auf zentral ausgelijstes Erbrechen. Acta biol. med. germ. 16: 650-657. HARNACK, E. (1874). Ueber die Wirkungen des Apomorphins am Saugethier und am Frosch. Archs exp. Path. Pharmak.
2: 254-306.
HENSIAK,J. F., CANNON,J. G. and BURKMAN,A. M. (1965). N-allylnorapormorphine.
J. med. Chem. 8:
557-559.
KOCH, M. V., CANNON,J. G. and BURKMAN,A. M. (1968). Centrally Acting Emetics, II. Norapomorphine and derivatives, J. med. Chem. 11: 977-981. SPRENGER,W. K., CANNON,J. G., BARMAN,B. K. and BURKMAN,A. M. (1969). Centrally Acting Emetics, III. Derivatives of p-naphthylamine, J. med. Chem. 12: 487490.