Antinociceptive effects of SC-39566, an opioid dipeptide arylalkylamide, in the Rhesus monkey.

This study evaluated the antinociceptive activity of an opioid dipeptide arylalkylamide, SC-39566 (2,6-dimethyl-L-tyrosinyl-D-alanyl-(3-phenyl-l-propyl)- amide), in the Rhesus monkey using the discrete trial, intermittent shock titration paradigm. I.m. administration of doses ranging from 12 to 24 mg/kg produced a dose-dependent increase in escape threshold and a dose-dependent rightward shift in the frequency distribution of responses to suprathreshold electrocutaneous stimuli. Although equivalent with respect to efficacy, SC-39566 was only one-fourth to one-sixth as potent as morphine in this paradigm. This study is the first report of the antinociceptive activity of an opioid dipeptide arylalkylamide after systemic administration in the primate.

Intermittent shock titration task in the rhesus monkey and its validity as an analgesiometric procedure.

This study addressed issues concerning the validity of the shock titration paradigm by using focal, pulsed electrocutaneous stimulation and including unavoidable suprathreshold intensity stimuli among titratable, threshold intensity trials. In saline-treated monkeys, the distribution of response latencies on suprathreshold intensity trials, and the relationships between stimulus intensity and response latency, percent response or trial duration were consistent with those expected of painful stimuli. Morphine (0.3-3 mg/kg i.m.), meperidine (0.3-3 mg/kg i.m.) and pentazocine (1-6 mg/kg i.m.) each dose-dependently increased escape thresholds, but did not increase response latency on titratable trials. In contrast, diazepam (0.12-0.5 mg/kg i.m.) produced a dose-dependent increase in escape threshold and a significant increase in response latency on titratable trials. Sedative anxiolytics with muscle relaxant properties could therefore be distinguished from opioid analgesics. Morphine, meperidine, pentazocine and diazepam also produced a dose-dependent rightward shift in the frequency distribution of responses to suprathreshold stimuli at doses below those that significantly increased escape threshold. Thus, the antinociceptive effect of an opioid analgesic was detectable in the monkey in the clinically effective dose range. This paradigm permits analysis of drug effects at both escape threshold and suprathreshold intensities of noxious stimuli. The concomitant measurement of escape threshold and response latency on titratable trials with analysis of the frequency distribution of responses on suprathreshold trials yields a sensitive and discriminating analgesiometric procedure with potential application to rodent, as well as primate, species.

Shock titration in the rhesus monkey: effects of opiate and nonopiate analgesics.

This study evaluated the antinociceptive effects of several opiate and nonopiate analgesics in the rhesus monkey using a discrete trial shock titration paradigm. Morphine sulfate (1, 5 and 10 mg/kg i.m.) and codeine sulfate (3, 10 and 30 mg/kg i.m.) produced a significant and dose-dependent increase in mean shock threshold that was not accompanied by a significant increase in mean response latency. The mean number of shocks terminated was significantly decreased at the highest dose of each opiate. Aspirin (100 and 300 mg/kg p.o.) or ibuprofen (200 mg/kg p.o.) did not significantly increase mean shock threshold or mean response latency or decrease mean number of shocks terminated. However, 6 mg/kg i.m. of 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol produced a significant increase in mean shock threshold and mean response latency with no significant effect on mean number of shocks terminated. The absence of any effects of a 2-mg/kg dose of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and the severe side effects produced by 10 mg/kg prevented determination of its dose-response relationship. Diazepam (0.5, 2 and 8 mg/kg i.m.) produced a significant, dose-dependent increase in mean shock threshold and a significant increase in mean response latency with no consistent or significant effect on mean number of shocks terminated. Doses of 2 and 8 mg/kg of diazepam also produced signs of ataxia. These results suggest that the discrete trial shock titration paradigm is suitable for demonstration of the antinociceptive effects of opiate and certain nonopiate analgesics, but not nonsteroidal anti-inflammatory analgesics in the rhesus monkey.

Biological properties of aspartame. I. Evaluation of central nervous system effects.

Aspartame was administered intragastrically to rodents at doses between 10 and 550 times the expected daily human intake to evaluate the effects on central nervous system function. No biologically meaningful effects were observed in either rats or mice following acute administration by the intragastric route. Aspartame administered as 9% of the diet (about 11 g/kg/day) for thirteen weeks to weanling rats altered the learning behavior of male rats. This effect of impaired learning behavior was nearly identical to that observed for an approximately equimolar amount of L-phenylalanine. The learning behavior of the female rats was not altered by either L-phenylalanine or aspartame at these extremely large doses. It was concluded that prolonged dietary ingestion of aspartame at levels approximately 550 times that expected for normal human daily ingestion was necessary to elicit a behavioral deficit.

Use of the butaclamol template in a search for antipsychotic agents with lessened side effects.

A number of molecular similarities between the antipsychotic agents butaclamol and clozapine were noted. Based on the premise that this was a strong indicator of a common mechanism of action (i.e., binding at the antagonist state of the dopamine receptor), a research approach was described. Three simplified analogues (4,8, and 12a) of butaclamol which still retained the molecular functionalities of the parent structure were synthesized and tested in the haloperidol receptor assay. 1-(5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene)-4-tert-butyl-4-piperidine (12a) displaced tritiated haloperidol with an IC50 value of 2.4 nM, as compared to a value of 0.5 nM for butaclamol However, when 12a was tested in vivo or in the spiroperidol receptor assay it was found to be considerably less potent.

Neuropharmacological and behavioral evaluation of prostaglandin E2 and 11-thiol-11-desoxy prostaglandin E2 in the mouse and rat.

Prostaglandin E2 (PGE2) and 11-thiol-11-desoxy Prostaglandin E2 (SHPGE2) were evaluated in a variety of behavioral and neuropharmacological procedures that are sensitive to neuroleptics. Clozapine (C), thioridazine (T), haloperidol (H), and fluphenazine (F) were also tested for comparison. All agents except T suppressed avoidance responses in trained rats at one or more doses without concurrently disrupting escape behavior. T, H, and F dose-responsively antagonized lesioned rat rotational behavior at nontoxic doses. T, H, and F induced catalepsy at doses considerably higher than those effective on rotational behavior. SHPGE2, PGE2, and C did not cause catalepsy and did not show statistically significant dose-response antagonism of rotational behavior at less than toxic doses. All agents tested blocked d-amphetamine-induced lethality and caused motor incoordination dose-responsively. SHPGE2, PGE2, C, and T caused statistically significant blockade of physostigmine-induced lethality. H and F were ineffective against physostigmine lethality. It was concluded that SHPGE2 and PGE2 demonstrated, qualitatively, a spectrum of neuroleptic like properties remarkably similar to C.

The pharmacology of SC-27166: a novel antidiarrheal agent.

SC-27166 is the result of continuing efforts to discover selective and orally active antidiarrheal agents. SC-27166, which is chemically unrelated to opiates or neuroleptics, possesses potent constipating and antidiarrheal activity in several animal models. Tolerance to the constipating actions of SC-27166 did not develop in mice. On the other hand, gut tolerance rapidly developed to morphine sulfate and loperamide. The basic mechanism of the antidiarrheal action of SC-27166 is a consequence of increased intestinal circular muscle contractile activity. Supportive pharmacological studies indicated that SC-27166 has equivocal analgesia in mice which is manifested at near toxic dose levels. SC-27166 was also evaluated for potential dependence liability in morphine abstinence-induced jumping in mice. The abstinence-induced jumping was suppressed to a far lesser extent by SC-27166 than by either loperamide or diphenoxylate at equal doses. SC-27166 was also devoid of anticbholinergic activity. When compared with the reference standards morphine and diphenoxylate, these pharmacological studies indicated that SC-27166 has a high degree of separation of undesirable central nervous system actions from its antidiarrheal properties and may have important therapeutic potential.

Antidiarrheal and central nervous system activities of SC-27166 (2-[3 - 5 - methyl - 1, 3, 4 - oxadiazol - 2 - yl) - 3, 3 - diphenylpropyl] - 2 - azabicyclo [2.2.2]octane), a new antidiarrheal agent, resulting from binding to opiate receptor sites of brain and myenteric plexus.

Pharmacological studies were performed to investigate the interaction of SC-27166 (2-[3-(5-methyl-1,3,4--oxadiazol-2-yl)-3,3-diphenylpropyl]-2-azabicyclo[2.2.2]octane), a new antidiarrheal agent, with opiate receptor sites in vitro and in vivo. Morphine, loperamide and SC-27166 inhibited the binding of [3H]naloxone to homogenates of guinea-pig brain and myenteric plexus and the inhibition was diminished in the presence of 100 mM Na+. Unlike that of morphine and [3H]naloxone itself, the binding of loperamide and SC-27166 was complex and Scatchard plots indicated the presence of low and high affinity sites for both compounds. Morphine, loperamide and SC-27166 inhibited the contractions of electrically driven longitudinal muscle from guinea-pig ileum and naloxone antagonized these effects. In the anesthetized dog, i.v. administration of morphine and SC-27166 enhanced the contractile activity of circular muscle in proximal and distal duodenum and distal ileum but duodenal longitudinal muscle was relaxed; these effects were completely reversed by subsequent administration of naloxone. In the rat, p.o. administration of loperamide and SC-27166 inhibited intestinal propulsion at doses considerably lower than were necessary to produce activity in the hot plate test; this specificity of action was not seen with morphine. In the rat, p.o. administration of loperamide and SC-27166 inhibited diarrhea at doses considerably lower than were necessary to produce withdrawal symptoms. The authors concluded that both loperamide and SC-27166 are specific antidiarrheal agents that produce both their central and antidiarrheal effects by binding to opiate receptor sites.

Synthesis of beta-spiro[pyrrolidinoindolines], their binding to the glycine receptor, and in vivo biological acitivity.

A series of beta-spiro[pyrrolidinoindolines], 3a-d, was prepared and evaluated for their ability to bind to the glycine receptor. These compounds were also tested in vivo to determine if they would produce convulsant or anxiolytic effects. The target indolines were chosen because they represent rings A, B, E, and a portion of ring C of strychnine. Results of this study indicate that, in this series, an acetylindoline in the endo configuration and a tertiary amine, such as that of the pyrrolidine ring nitrogen, are required for biological activity. In all of the cases studied, the activity was of a convulsant rather than a relaxant nature. Excellent correlation was found to exist between the binding affinities to the strychnine site of the glycine receptor and clonic convulsions (ED50) and death (LD50) in the mouse.