Abstract
SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)-5-H-benzo[5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminic potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement ofin vivo 3H-mepyramine binding in mouse brain andin vitro 3H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally.
SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
F.E. Roth andI.I.A. Tabachnick, Histamine and antihistamines. InDrill's Pharmacology in Medicine, 4th edn pp. 995–1020 (Ed.J.R. Dipalma). McGraw-Hill, Inc., Philadelphia 1971.
K.J. Melville, Antihistamine drugs, InHistamine and Antihistamine, vol. 1, pp. 156–157 (Ed.M. Schacter), Pergamon Press, New York 1973.
M.L. Brandon andM. Weiner Clinical investigation of terfenadine, a non-sedating antihistamine, Ann. Allergy44, 71–75 (1980).
J. Van Wauwe, F. Awouters, C.J. Niemegeers, F. Janssen, J.M. Van Nueten andP.A.J. Janssen,In vivo pharmacology of astemizole, a new type of H 1-antihistaminic compound, Arch. int. Pharmacodyn. Thér.251, 39–51 (1981).
C.H. Clarke andA.N. Nicholson,Performance studies with antihistamines, Br. J. Clin. Pharmac.6, 31–35 (1978).
V.K. Kulshrestha, P.P. Gupta, P. Turner andJ. Wadsworth,Some clinical pharmacological studies with terfenadine, a new antihistamine drug, Br. J. Clin. Pharmac.6, 25–29 (1978).
L. Moser, K.J. Huther, J. Koch-Weser andP.V. Lundt,Effects of terfenadine and diphenhydramine alone or in combination with diazepam or alcohol on psychomotor performance and subjective feeling, Eur. J. Clin. Pharmac.14, 417–423 (1978).
D.J. Finney,Probit Analysis, 2nd edn. Cambridge University Press 1962.
K.A. Brownlee,Statistical Theory and Methodology in Science and Engineering, 2nd edn., pp. 346–349. Wiley and Sons, New York 1965.
S. Irwin, Drug screening and evaluation of new drugs in animals. InAnimal and Clinical Pharmacologic Techniques in Drug Evaluation, pp. 36–54 (EdsJ.M. Nodine andP.E. Siegler). Year Book Medical Publishers Inc., Chicago 1964.
J.T. Litchfield andF. Wilcoxon,A simplified method of evaluating dose effect experiments, J. Pharmac. Exp. Ther.96, 99–113 (1949).
J. Toman, E. Swinyard andL.S. Goodman,Properties of maximal seizures and their alteration by anticonvulsant drugs and other agents, J. Neurophysiol.9, 231–239 (1946).
L.C. Hendershot andS. Forsaith,Antagonism in the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and non-analgesics, J. Pharmac. Exp. Ther.125, 237–240 (1959).
R. Koster, M. Anderson andE.J. DeBeer,Acetic acid for analgesic screening, Fedn Proc.18, 412 (1959).
H.O.J. Collier, L.C. Dineen, C.A. Johnson andC. Schneider,The abdominal constriction response and its suppression by analgesic drugs in the mouse, Br. J. Pharmac.32, 295–310 (1968).
D.C. U'Prichard, D.A. Greenberg, P.P. Sheehan andS.H. Snyder,Tricyclic antidepressants: therapeutic properties and affinity for alphanoradrenergic receptor binding sites in the brain, Science, N.Y.199, 197–198 (1978).
V.T. Tran, R.S.L. Chang andS.H. Snyder,Histamine H 1 receptors identified in mammalian brain membranes with [3H] mepyramine, Proc. natn. Acad. Sci. USA75, 6290–6294 (1978).
D.W. Dunnett,A multiple comparison procedure for comparing several treatments with a control, J. Am. Statist. Ass50, 1096–1121 (1955).
J. Halperin andL.C. Iorio,Protection from shock-induced seizures as a measure of hypnotic potency of drugs, Pharmac. Biochem. Behaviour13, 299–301 (1980).
J.B. Malick andA. Barnett,Central versus peripheral anticholinergic activity as assessed by two in vivo procedures in mice, J. Pharm. Sci.64, 1066–1068 (1975).
S.J. Peroutka, D.C. U'Prichard, D.A. Greenberg andS.H. Snyder,Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain, Neuropharmacology16, 549–555 (1957).
H.S. Ahn, R.F. Petruzzi andE.A. Peets,Antihistamines: Therapeutic properties and affinities for [ 3H] mepyramine and [3H] WB4101 binding sites in the brain, Fedn Proc.39, 389 (1980).
T.T. Quach, C.R. Duchemin, C. Rose andJ.C. Schwartz,In vivo occupation of cerebral histamine H 1 receptors evaluated with3H-mepyramine may predict sedative properties of psychotropic drugs Eur. J. Pharmac.60, 391–392, (1979).
T. Seppala andK. Savolainen Effect of astemizole on human psychomotor performance, Curr. Therap. Res.31, 638–644 (1982).
A.N. Nicholson andB.M. Stone,Performance studies with the H 1-histamine receptor antagonists, astemizole and terfenadine, Br. J. Clin. Pharmac.13, 199–202 (1982).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Barnett, A., Iorio, L.C., Kreutner, W. et al. Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine. Agents and Actions 14, 590–597 (1984). https://doi.org/10.1007/BF01978891
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01978891