PubMed · 6546323
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K E Light. 1984-01-06. Analyzing nonlinear scatchard plots.. https://doi.org/10.1126/science.6546323
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The potency of hallucinogenic amphetamine derivatives of the 1-(2,5-dimethoxy-4-alkylphenyl)-2-aminopropane type drops dramatically when the length of the 4-alkyl substituent exceeds propyl or when the substituent is branched. This investigation was directed toward evaluating changes in behavioral and biochemical pharmacology resulting from introducing chirality into the 4-alkyl group of such analogues. Two diastereoisomeric derivatives of this class containing a 4-(R or S)-2-butyl substituent, 11a,b, respectively, were studied. A slight but nonsignificant potency difference in d-lysergic acid diethylamide tartrate (LSD)-like discriminative stimulus properties and equal affinity for [125I]-(R)-(2,5-dimethoxy-4-iodophenyl) isopropylamine-labeled serotonin 5-HT2A/C radioligand-binding sites were observed. Thus, the portion of the receptor that interacts with the 4-alkyl substituent on hallucinogenic amphetamines does not present a highly asymmetric environment to the ligand. However, since both test drugs had higher binding affinity but lower LSD-like behavioral potency than the prototype compound with a 4-methyl group ((2,5-dimethoxy-4-methylphenyl)isopropylamine, 2), 11a,b may differ in their receptor agonist efficacy from more behaviorally active compounds such as 2.
These studies examined the effects of a 21-day treatment regime with either the tricyclic antidepressant, desmethylimipramine (DMI), or the selective 5-HT uptake inhibitor, fluoxetine, on 5-HT2 receptors in rat brain, as assessed by selective agonist-mediated c-fos gene expression. Chronic, but not acute, treatment with fluoxetine (10 mg/kg, i.p. for 21 days) resulted in supersensitization of the response to an acute challenge (4 mg/kg, i.p.) with the selective 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), both in frontal cortex and in hippocampus. Chronic treatment with DMI (10 mg/kg, i.p. for 21 days) resulted in a significant desensitization of the response to DOI. These findings are discussed in relation to the possible modes of action of these two clinically useful agents.
Hippocampal and cortical EEG recordings in rats were used to monitor the in vivo modulation by lithium of responses to agonists for 5HT2/5HT1c serotonergic (DOI) and cholinergic (pilocarpine) receptors and the influence of inositol administration. Administration of DOI (8 mg/kg) or pilocarpine (30 mg/kg) to rats pretreated with lithium acutely (3 mmol/kg) or chronically (dietary, 4 weeks) resulted in seizures, whereas these doses did not cause seizures without lithium pretreatment. This indicated that lithium most likely affects a signal transduction process common to both systems, which is the phosphoinositide second messenger system. To examine the potential influence of altered inositol levels on these responses, we tested the effects of infusions (10 mg, i.c.v.) of myo-inositol, a precursor of phosphoinositide synthesis, and of epi-inositol, an isomer not used for phosphoinositide synthesis. Administration of myo-inositol (10 mg) slightly reduced the incidence of seizures induced by acute lithium plus DOI but almost completely blocked seizures induced by acute lithium plus pilocarpine. This was surprising since seizures induced by acute lithium plus DOI were less severe than those after acute lithium plus pilocarpine, but myo-inositol was more effective in blocking the latter. Epi-inositol also blocked seizures under both conditions but it was less effective than myo-inositol after treatment with acute lithium plus pilocarpine. The latencies to seizures and/or severity of seizures were potentiated more by chronic than acute lithium pretreatment with both DOI and pilocarpine, but attenuation by myo-inositol was less with each agonist after chronic lithium compared with acute lithium treatment. Peripheral administration of a high dose of myo-inositol blocked seizures induced by acute lithium plus pilocarpine, but the inositol treatment itself was toxic and caused seizures prior to pilocarpine administration, so the mechanism of action cannot simply be attributed to increased brain inositol levels. These results demonstrate that lithium modulates the in vivo responses to DOI and pilocarpine, most probably through an effect on the phosphoinositide signal transduction system. They also show that centrally administered myo-inositol modifies responses to these agents, but the effectiveness of epi-inositol and other results leave unclear the mechanistic basis of its actions.