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482 The relationship between chemical structure and CNS-depressant activity of basic ketones related to haloperidol
144 481
Abstracts of Papers
On the Unusual Chemical Structure of Piriuitrarnide (R 3365), a Potent Analgesic. C. v.4~ DE U~ESTERINGH (Belgium). The results of a systematic investigation on the qualitative and quantitative influence of modifications on 4 different points of the Pethidine molecule on the pharmacological properties arc discussed shortly. Most of the compounds have either analgesic or neuroleptic properties, the type of activity depending largely on the nature of ;he substituent on the ~2~ nitroeen atom and to a lesser degree on the other modifications. During this investigation it was found that substitution of the 4-phenyl group by other groups of basic, non-aromatic character (e.g. piperidine), in combination with other modifications, gives rise to compounds with novel properties. The most interesting of these compounds, Pirinitramide (R 3365; I) is a potent analgesic, about 5 times as In dogs, however, R 3365 is active as pethidine. devoid of morphine-like physical dependence capacity. The pharmacology of this compound is discussed in some more detail.
CN
L
482 The Relationship between Chemical and CNS-Depressant Activity Ketones Related to Haloperidol. (Belgium).
Structure of &sic P. JAP\‘SSEN
A series of over 1500 basic ketones of general structure I were synthetized and screened for CNSdepressant activity.
Many butyrophenones related to Haloperidol (II) were found to be potent neuroleptic drugs, pharmacologically similar to the phenothiazine derivatives of the chlorpromazine type, whereas many propiophenones related to compound R 951 (III) are potent morphine-like analgesics. The quality and the potency of the pharmacological effects produced by compounds of structure I depend on the nature of L, alkyl and NAA’. These relationships will be discussed in some detail. Ph armacologie MICHEL, Jy TRON-LOISEL
des IodosynCphrines. KLEPPING, R. TRUCI~OT (France).
et
R. H.
L’iodation en 3 et 3:5 renforce et prolonge les principales proprietes sympathomimttiques de la SynCphrine (S). Chez ke lapin, la 3-iodosynephrine (MIS) presente un pouvoir hypertenseur double et la 3:5_diiodosynCphrine (DIS) quadruple de celui de (S); chez le chien (MIS) n’est guerc plus actif que (S) tandis que (DE) montre un effect tension& double. A fleche hypertensive Cgale, la durte de la reponse dorm& par (DIS) est quatre fois plus allongee que celle de l’adrenaline. Des injections rep&tees n’entrainent pas de diminution de la reponsc pressive et (MIS), mais surtout (DIS) en perfusion continue, produisent une elevation trnsionnelle importante, soutenue, sans compensam&mes effets tion ni hypotension secondaire; accompagnts d’hypoventilation pulmonaire et vasoconstriction renale chez le chien amyele a surrenales exclues. On observe une inhibition augment& en intensite et en duree de la motricite de l’intestin isole de lapin proportionnellement P Les qualites sympathomimetiques l’effet tenseur. des iodosynephrines sont done caracterisees par une activite peripherique. Le rythme cardiaque, peu influence par (MIS), est ncttement ralenti par (DIS) ; atropine et section des “agues attenuaent cc ralentissement sans le supprimer. La consommation d’oxygene augmentee par (S) n’est pas modifiee par (MIS) et de faibles doses de (DIS) ; de fortes doses de (DIS) la diminuent chcz le rat normal ou thyreoprive.
Pharmacology of Iodosynephrines. R. ~UICHEL, J. KLEPPING, R. TRCJCHOTand H. TRON-LOISEL (France). Iodination on 3 and 3-5 positions reinforces and prolongs the main sympathomimetic properties of Synephrine (S). In the rabbit, 3-iodosynephrine (MIS) shows twice the hypertensive potency and 3 :5_diiodosynephrine (DIS) four times the potency At equal hypertensive levels, the duraof (S). tion of the response due to (DIS) is four times greater than that due to adrenalin. Repeated injections do not involve in a decrease the pressor response, and (MIS) and particularly (DIS) continues to produce a marked rise in blood pressure during continuous perfusion; this effect is constant without compensa-
Abstracts of Papers
On the Unusual Chemical Structure of Piriuitrarnide (R 3365), a Potent Analgesic. C. v.4~ DE U~ESTERINGH (Belgium). The results of a systematic investigation on the qualitative and quantitative influence of modifications on 4 different points of the Pethidine molecule on the pharmacological properties arc discussed shortly. Most of the compounds have either analgesic or neuroleptic properties, the type of activity depending largely on the nature of ;he substituent on the ~2~ nitroeen atom and to a lesser degree on the other modifications. During this investigation it was found that substitution of the 4-phenyl group by other groups of basic, non-aromatic character (e.g. piperidine), in combination with other modifications, gives rise to compounds with novel properties. The most interesting of these compounds, Pirinitramide (R 3365; I) is a potent analgesic, about 5 times as In dogs, however, R 3365 is active as pethidine. devoid of morphine-like physical dependence capacity. The pharmacology of this compound is discussed in some more detail.
CN
L
482 The Relationship between Chemical and CNS-Depressant Activity Ketones Related to Haloperidol. (Belgium).
Structure of &sic P. JAP\‘SSEN
A series of over 1500 basic ketones of general structure I were synthetized and screened for CNSdepressant activity.
Many butyrophenones related to Haloperidol (II) were found to be potent neuroleptic drugs, pharmacologically similar to the phenothiazine derivatives of the chlorpromazine type, whereas many propiophenones related to compound R 951 (III) are potent morphine-like analgesics. The quality and the potency of the pharmacological effects produced by compounds of structure I depend on the nature of L, alkyl and NAA’. These relationships will be discussed in some detail. Ph armacologie MICHEL, Jy TRON-LOISEL
des IodosynCphrines. KLEPPING, R. TRUCI~OT (France).
et
R. H.
L’iodation en 3 et 3:5 renforce et prolonge les principales proprietes sympathomimttiques de la SynCphrine (S). Chez ke lapin, la 3-iodosynephrine (MIS) presente un pouvoir hypertenseur double et la 3:5_diiodosynCphrine (DIS) quadruple de celui de (S); chez le chien (MIS) n’est guerc plus actif que (S) tandis que (DE) montre un effect tension& double. A fleche hypertensive Cgale, la durte de la reponse dorm& par (DIS) est quatre fois plus allongee que celle de l’adrenaline. Des injections rep&tees n’entrainent pas de diminution de la reponsc pressive et (MIS), mais surtout (DIS) en perfusion continue, produisent une elevation trnsionnelle importante, soutenue, sans compensam&mes effets tion ni hypotension secondaire; accompagnts d’hypoventilation pulmonaire et vasoconstriction renale chez le chien amyele a surrenales exclues. On observe une inhibition augment& en intensite et en duree de la motricite de l’intestin isole de lapin proportionnellement P Les qualites sympathomimetiques l’effet tenseur. des iodosynephrines sont done caracterisees par une activite peripherique. Le rythme cardiaque, peu influence par (MIS), est ncttement ralenti par (DIS) ; atropine et section des “agues attenuaent cc ralentissement sans le supprimer. La consommation d’oxygene augmentee par (S) n’est pas modifiee par (MIS) et de faibles doses de (DIS) ; de fortes doses de (DIS) la diminuent chcz le rat normal ou thyreoprive.
Pharmacology of Iodosynephrines. R. ~UICHEL, J. KLEPPING, R. TRCJCHOTand H. TRON-LOISEL (France). Iodination on 3 and 3-5 positions reinforces and prolongs the main sympathomimetic properties of Synephrine (S). In the rabbit, 3-iodosynephrine (MIS) shows twice the hypertensive potency and 3 :5_diiodosynephrine (DIS) four times the potency At equal hypertensive levels, the duraof (S). tion of the response due to (DIS) is four times greater than that due to adrenalin. Repeated injections do not involve in a decrease the pressor response, and (MIS) and particularly (DIS) continues to produce a marked rise in blood pressure during continuous perfusion; this effect is constant without compensa-