Daniel Luttinger

C-ATTACHED AMINOALKYLINDOLES : POTENT CANNABINOID MIMETICS

Abstract Aminoalkylindoles (AAIs) with potent cannabinoid agonist activity have been synthesized where the aminoalkyl chain is attached to the indole ring via a carbon atom of the cyclic amine.

Determination of antinociceptive efficacy of drugs in mice using different water temperatures in a tail-immersion test

A variety of analgesic drugs were tested for their ability to alter the response to noxious stimuli of differing severity in an attempt to develop a procedure to evaluate differences in efficacy of different analgesics. The severity of a noxious stimuli delivered to mice was varied by immersing the mouse tails in water maintained at 45, 50, 55 degrees C. As has been previously observed, the opiate analgesics morphine and nalorphine were active at all temperatures. Pentazocine was active at 45 and 50 degrees C, but not at 55 degrees C. The cyclooxygenase inhibitors tested showed a wide variety of activity. Naproxen was active at all temperatures. Zomepirac was active at 45 and 50 degrees C, but not 55 degrees C. Acetaminophen, ibuprofen, and fenoprofen were active at 45 degrees C, but not at higher temperatures. Aspirin and indomethacin were inactive at all temperatures tested. These results roughly paralleled the differences in the severity of pain for which these analgesics are effective.

The effects of serotonin antagonists in a behavioral despair procedure in mice

Six serotonin antagonists (pizotifen, mianserin, cyproheptadine, ketanserin, trazodone and methysergide) were tested in mice in a behavioral despair procedure. The behavioral despair procedure detects most antidepressant compounds. Pizotifen, mianserin and cyproheptadine were found to be active and the others were inactive. The serotonin binding potency at serotonin1 or serotonin2 receptors, or the ratio of potency at these receptors did not correlate with activity in the behavioral despair procedure. However, the serotonin antagonists that were active in the behavioral despair procedure were all found to be potent antagonists at histamine1 receptors. It is suggested that the activity of some serotonin antagonists in the behavioral despair procedure is best explained by their antihistaminergic potency.

Morpholinoalkylindenes as antinociceptive agents: Novel cannabinoid receptor agonists

Abstract Indence analogs of pravadoline exhibited antinociceptive activity in several animal models. The inhibition of prostaglandin (PG) synthesis in mouse brain microsomes was diminished in these pravadoline analogs, but they were potent in inhibiting electrically stimulated contractions in the mouse vas deferens (MVD) preparations. Binding studies with ligand WIN 55212-2 have aided to demonstrate that the morpholinoalkyl-indene binding site is functionally equivalent with cannabinoid binding site. The antinociceptive activity of the indene derivatives appears to be mediated by increased affinity for the cannabinoid receptor.

Alpha2-adrenergic antagonists effect on amphetamine-induced behaviors

The effects of alpha 2-adrenergic antagonists on amphetamine-induced locomotion and stereotypy were studied in mice. Six alpha 2-antagonists (i.e., yohimbine, rauwolscine, piperoxan, tolazoline, RX781094, and RS21361) selectively attenuated amphetamine-induced increases in locomotion at doses which did not effect amphetamine-induced stereotypies. Higher doses of the antagonists which attenuated baseline stereotypies also attenuated amphetamine-induced increases in stereotypies. The effect of the alpha 2-antagonists was qualitatively similar to that observed with the atypical antipsychotic clozapine. Furthermore, the in vivo relative potency of the alpha 2-antagonists in the present study was comparable to that reported in other studies. These results suggest that alpha 2-adrenergic receptors may modulate the effects of amphetamine on locomotion in mice.

σ Receptor binding affinity and inhibition of apomorphine-induced climbing

Several relatively selective compounds with affinity for the sigma binding site were assessed for their ability to inhibit apomorphine-induced climbing in the mouse. Although, the majority of compounds inhibited apomorphine-induced climbing, there was no correlation between the ability to inhibit climbing and potency in sigma binding assays using [3H]1,3-di-o-tolylguanidine (DTG) or [3H](+)-pentazocine as ligands. The potency of the compounds to inhibit binding to muscarinic M1 or M2 receptors correlated with the potency to inhibit apomorphine-induced climbing. However, several of the compounds that inhibit climbing had microM affinity at muscarinic receptors. Whether these concentrations were achieved in vivo is unclear. Our data suggest that sigma activity per se is not responsible for inhibition of apomorphine-induced climbing.

Chapter 3 Antidepressant Agents

Publisher Summary The major concerns in current anti-depression therapy are delayed onset of activity, less than ideal efficacy, the importance of proper patient selection, and biochemical predictors of treatment response and side effects. There are various obstacles. Urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels appear not to predict the treatment response. Platelet serotonin (5-HT) uptake does not show a circadian rhythm in delusional and nondelusional depressed patients unlike healthy subjects. Placebo responders are likely to be nonendogenous depressives and have a shorter length of illness with less severe symptomatology. The search has continued to identify new “second generation” monoamine uptake inhibitors and to identify selective inhibitors of monoamine oxidase A or B. The α 2 -adrenergic antagonists offer a new therapy for the treatment of depression, although the efficacy of these agents is yet to be studied conclusively in human. Data pertaining to the effects of depressive illness and treatment with anti-depressants on %-adrenergic receptors have been studied. Platelet α 2 -adrenoceptors appeared to be elevated in drug-free depressed patients and anti-depressant treatment returned these values to normal. A more rapid onset of anti-depressant effect and fewer adverse drug effects than existing therapeutic agents remain as the important hurdles for the newer agents undergoing clinical evaluation.