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Brain injury and early catecholamine mobilization
86
TIPS-
March 1984
.solely relying on experimentally observed conformations. Once more, it appears that conformational analysis in drug design and pharmacophore identification should be performed in a well-understood manner using experimental and theoretical approaches.
-..P
,i,%,
J. P. "I*()I.LENAERE
! ! I I
-_
, .
,
67 nm
~_z_Q
85 n m
Fig. 2. Muscarinic phannacophore conformanon Of aceo'lcholme.
tire to that of 5-methylfurmethide can be rationalized on the basis of their PC distances. The conformation of acetylcholine employed in the muscarinic pharmacophore is characterized by "r~ = 189% %, = 132° ('r = 117° , PC = 85 nm) and is depicted in Fig. 2. Finallx. the large discrepancies be-
Departmo~t of Theoretical Medicinal Chemi~tr),, Jamsen Pharmactmtiea Research I.aboratories, B2340 Beerse, Belgium.
J
tween the crystallographic "r~ an,] "rz values and those in the active muscarinic conformation are worth mentioning. It appears that only ACTM shows the best agreement between crystal and pharmacophore geometry with less than 10° difference between the two sets of torsion apgles. These great discrepancies quite convincingly show the uselessness of
Brain injury and early catecholamine mobilization A recent paper ~ given at the Fifth Catccholamine Symposium (held at Grteborg. Sweden, 12-16 June !'983) has reinforced earlier suggestions (see e.g. Ref. 2) that catecholaminergic s~sterns are involved in the recovery from motor cortex iniu~'. The authors trained rats and cats to run across a narrow beam and determined the success rate at negotiating ~he beam both before and at different times after unilateral ablation of the s e n ~ r i m o t o r cortex. The animals were unable to negotiate the beam directly alter the sensorimotor ablation, although a certain amount of recover~. was found two weeks (in rats) and three months (in cats) after the ablation ~. Interestingly. in the rat. a single dose of D-amphetamine (2 mg k g ~ i.p.) given 24 h after the operation produced a long-lasting recoveu, which was blocked either by haloperidol (0.4 mg k g - I i.p. ) or by restraining the animals ~'a. Such a facilitatory, effect of amphetamine on
~.~ !(~4. ~
~
~
Reading list I Baker, R. W., Chothia, C, H., Pauling, P. and Petcher, T. J. (1971) Nature (London~ 2311, 439-445 2 Tollenaere, J. P. (1981) Trend~ Pharmacol. Sci. 2. 27~275 3 Tollenaetc, J. P., Moereels, tt. and Raymaekers, L. A. (1981) in Dn~g Dcs'ign (Ari/~ns, E. J., ed.), Vol, 10, pp. 71-118, Academtc
Press, New York 4 Schulman,J. M.. Sabio, M. L. and Disch. R. L. (1983) J. Med. Chem. 26. 817--823 5 Tollenaerc.J. P.. Moereeis.H. and Raymaekers, L. A. (1979) Atlas of the Three-Dimemmnal Structure of Drugs', El~vier BiomedicalPress. Amsterdam biochemical and histochemicai measurements together with a ~ f i e s of other motor function tests, have direct clinical relevance to the treatment of patients suffering from brain injury brought about by stroke, since the,,, would suggest that either restraint or administration of adrenergic antagonists to these patients may hinder any recoveD of motor function ~.
motor performance after unilateral motor cortex ablation has been demonstrated a l ~ for the cat-', although in this case the amphetamine was not given until 4 days after the operation and the effect was only temporary. Further evidence for the enhanced recovery from behavC t t R I S T O P I t E R J. F O W L E R A N D ioural aberrations caused by brain TREVOR ARCttER damage as a result of an early mobilization of the catecholamine systems comes Research and Develolmwnt Laboratorie,i, Astra from studies by Gage and Olton 4 who 1,dkemedel A B, S-151 85 SOdertid/e, Sweden. demonstrated that t-dopa (together ~ith a peripheral dopa decarboxylase inhibitor) reduced hyper-reactivity induced by Reading list septal lesions in rats. I Feeney, D. M., Boyeson, M. G., tlovda, D. A. On the other hand. it has been reand Salo. A. A. (1983) 5th Catecholamine ported that admini:,tration of the adrenSymposium, GOteborg, Sweden, Abstract No. ergic antagoni,a phenoxybenzamine to t 146. Published as a supplement to Vol. 7 of Progr. Neuropy~hopharmacol. Biol. Psychmt. cats which had recovered from unilateral motor cortex ablation resulted in a re- 2 Feeney, D, M. and Hovda, D. A. (1983) Pvychopharmacology 79, 67-71 lapse in their motor performance as 3 Feeney, D. M, Gonz.'dez. A. and Law, W A. assessed by the beam test ~. These results, (1983) Science 217, 855-857 which would be considerably strength- 4 Gage, F. H. and OIton, D. S. (It~76) Behav. Biol. 17, 21.L-218 ened by the introduction of parallel
~.v. Amsterdam 01('~5- 6147~t4,'$1~.tlll
TIPS-
March 1984
.solely relying on experimentally observed conformations. Once more, it appears that conformational analysis in drug design and pharmacophore identification should be performed in a well-understood manner using experimental and theoretical approaches.
-..P
,i,%,
J. P. "I*()I.LENAERE
! ! I I
-_
, .
,
67 nm
~_z_Q
85 n m
Fig. 2. Muscarinic phannacophore conformanon Of aceo'lcholme.
tire to that of 5-methylfurmethide can be rationalized on the basis of their PC distances. The conformation of acetylcholine employed in the muscarinic pharmacophore is characterized by "r~ = 189% %, = 132° ('r = 117° , PC = 85 nm) and is depicted in Fig. 2. Finallx. the large discrepancies be-
Departmo~t of Theoretical Medicinal Chemi~tr),, Jamsen Pharmactmtiea Research I.aboratories, B2340 Beerse, Belgium.
J
tween the crystallographic "r~ an,] "rz values and those in the active muscarinic conformation are worth mentioning. It appears that only ACTM shows the best agreement between crystal and pharmacophore geometry with less than 10° difference between the two sets of torsion apgles. These great discrepancies quite convincingly show the uselessness of
Brain injury and early catecholamine mobilization A recent paper ~ given at the Fifth Catccholamine Symposium (held at Grteborg. Sweden, 12-16 June !'983) has reinforced earlier suggestions (see e.g. Ref. 2) that catecholaminergic s~sterns are involved in the recovery from motor cortex iniu~'. The authors trained rats and cats to run across a narrow beam and determined the success rate at negotiating ~he beam both before and at different times after unilateral ablation of the s e n ~ r i m o t o r cortex. The animals were unable to negotiate the beam directly alter the sensorimotor ablation, although a certain amount of recover~. was found two weeks (in rats) and three months (in cats) after the ablation ~. Interestingly. in the rat. a single dose of D-amphetamine (2 mg k g ~ i.p.) given 24 h after the operation produced a long-lasting recoveu, which was blocked either by haloperidol (0.4 mg k g - I i.p. ) or by restraining the animals ~'a. Such a facilitatory, effect of amphetamine on
~.~ !(~4. ~
~
~
Reading list I Baker, R. W., Chothia, C, H., Pauling, P. and Petcher, T. J. (1971) Nature (London~ 2311, 439-445 2 Tollenaere, J. P. (1981) Trend~ Pharmacol. Sci. 2. 27~275 3 Tollenaetc, J. P., Moereels, tt. and Raymaekers, L. A. (1981) in Dn~g Dcs'ign (Ari/~ns, E. J., ed.), Vol, 10, pp. 71-118, Academtc
Press, New York 4 Schulman,J. M.. Sabio, M. L. and Disch. R. L. (1983) J. Med. Chem. 26. 817--823 5 Tollenaerc.J. P.. Moereeis.H. and Raymaekers, L. A. (1979) Atlas of the Three-Dimemmnal Structure of Drugs', El~vier BiomedicalPress. Amsterdam biochemical and histochemicai measurements together with a ~ f i e s of other motor function tests, have direct clinical relevance to the treatment of patients suffering from brain injury brought about by stroke, since the,,, would suggest that either restraint or administration of adrenergic antagonists to these patients may hinder any recoveD of motor function ~.
motor performance after unilateral motor cortex ablation has been demonstrated a l ~ for the cat-', although in this case the amphetamine was not given until 4 days after the operation and the effect was only temporary. Further evidence for the enhanced recovery from behavC t t R I S T O P I t E R J. F O W L E R A N D ioural aberrations caused by brain TREVOR ARCttER damage as a result of an early mobilization of the catecholamine systems comes Research and Develolmwnt Laboratorie,i, Astra from studies by Gage and Olton 4 who 1,dkemedel A B, S-151 85 SOdertid/e, Sweden. demonstrated that t-dopa (together ~ith a peripheral dopa decarboxylase inhibitor) reduced hyper-reactivity induced by Reading list septal lesions in rats. I Feeney, D. M., Boyeson, M. G., tlovda, D. A. On the other hand. it has been reand Salo. A. A. (1983) 5th Catecholamine ported that admini:,tration of the adrenSymposium, GOteborg, Sweden, Abstract No. ergic antagoni,a phenoxybenzamine to t 146. Published as a supplement to Vol. 7 of Progr. Neuropy~hopharmacol. Biol. Psychmt. cats which had recovered from unilateral motor cortex ablation resulted in a re- 2 Feeney, D, M. and Hovda, D. A. (1983) Pvychopharmacology 79, 67-71 lapse in their motor performance as 3 Feeney, D. M, Gonz.'dez. A. and Law, W A. assessed by the beam test ~. These results, (1983) Science 217, 855-857 which would be considerably strength- 4 Gage, F. H. and OIton, D. S. (It~76) Behav. Biol. 17, 21.L-218 ened by the introduction of parallel
~.v. Amsterdam 01('~5- 6147~t4,'$1~.tlll