ABSTRACT
Delta(9)-Tetrahydrocannabinol was injected daily, in increasing doses, in pigeons under a multiple schedule of food presentation. Within a week, a dose that initially abolished responding completely was without effect. This dose was gradually increased to 20 times its original value without disrupting the behavior. No withdrawal syndrome was detected when the cannabinol was discontinued.
ABSTRACT
Molecular modelling studies suggested the synthesis of cis-1,3,4,6,7, 11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (7a) as a rigid analogue of the atypical antidepressant mianserin. Acylation of 2,2-diphenylethylamine with chloroacetyl chloride gives the chloroacetamide (2). Cyclization of 2 with P2O5 in xylene provides 1-(chloromethyl)-3,4-dihydro-4-phenylisoquinoline (3). Amination of 3, followed by reduction, gives the isomeric (aminomethyl)tetrahydroisoquinolines (4a and 5). Treatment of 4a with diethyl oxalate, followed by reduction of the diamide with borane, provides 7a. A variety of N-substituted, aromatic substituted, and optically resolved derivatives were prepared and evaluated for anticholinergic, antihistaminic, and antidepressant activity. In particular, the target cis isomer 7a as predicted from the modelling studies appears to possess excellent atypical antidepressant activity. This activity resides in the (+)-S,S optical isomer 10, which has the same absolute configuration as (+)-mianserin.
Subject(s)
Antidepressive Agents/chemical synthesis , Isoquinolines/chemical synthesis , Animals , Brain/metabolism , Dogs , Imipramine/pharmacology , Isoquinolines/pharmacology , Mianserin/analogs & derivatives , Mianserin/pharmacology , Models, Molecular , Pyrilamine/metabolism , Quinuclidinyl Benzilate/metabolism , Rats , Receptors, Cholinergic/metabolism , Receptors, Histamine/metabolismABSTRACT
Anticonvulsant tests in mice revealed specific, potent actions of remacemide for protection of mice against maximal electroshock seizures (MES). Comparisons of oral efficacy to reference compounds yielded the following ED50 values (expressed as mg/kg): remacemide = 33, phenytoin = 11, phenobarbital = 20, carbamazepine = 13 and valproate = 631. The duration for protection by remacemide was longer than carbamazepine or valproate, but shorter than phenytoin or phenobarbital. In neural impairment tests (inverted screen or rotorod) to determine the oral toxic dose 50 (TD50) the following therapeutic indices (TD50/ED50) were obtained: (1) inverted screen--remacemide = 17.6, phenytoin = 57.4, phenobarbital = 5.1, carbamazepine = 10.2, and valproate = greater than 3; and (2) rotorod--remacemide = 5.6, phenytoin = 9.6, phenobarbital 4.8, and valproate = 1.9. Remacemide was devoid of sedative actions and possessed a favorable 28.1 margin of safety value (median estimated lethal dose/ED50 for MES). An intermediate potency against either audiogenic- or N-methyl-D-aspartate-induced seizures was exhibited by remacemide. Tolerance to MES was not apparent after 5 days of oral daily dosing of remacemide. Remacemide was inactive in vitro against gamma-aminobutyrate or benzodiazepine receptors and adenosine uptake mechanisms. Therapeutic utility for generalized tonic/clonic seizures is predicted for remacemide.
Subject(s)
Acetamides/pharmacology , Anticonvulsants/pharmacology , Seizures/physiopathology , Acetamides/adverse effects , Acetamides/toxicity , Administration, Oral , Animals , Dose-Response Relationship, Drug , Electroshock , Hypnotics and Sedatives , Injections, Intraperitoneal , Lethal Dose 50 , Male , Mice , Mice, Inbred Strains/physiology , Nervous System/drug effects , Phenobarbital/toxicity , Polyethylene Glycols , Receptors, GABA-A/metabolism , Seizures/prevention & control , Solutions , WaterABSTRACT
Passive avoidance retention and cortical [H3]-quinuclidinyl benzilate (QNB) binding were examined in rats that were chronically treated with diisopropylfluorophosphate (DFP), an irreversible acetylcholinersterase inhibitor. Retention of a passive avoidance response in DFP-treated rats was significantly lower when compared to vehicle-treated controls. Passive-avoidance retention decreased from 93% in control animals to 68% in DFP-treated rats. QNB binding studies revealed the density of muscarinic receptors in cortical homogenates was significantly reduced from 0.95 +/- 0.04 pmole/mg protein in controls to 0.72 +/- 0.04 pmole/m protein in DFP-treated rats. Scatchard analysis of QNB binding curves did not reveal a decrease in affinity of muscarinic receptors for QNB. Based on data that DFP causes a reduction in cholinergic receptors, this study supports the hypothesis that central cholinergic receptors are associated with mechanisms involved in memory storage.