ABSTRACT
Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase clinical studies. However, relatively little is known about the behavioral and neural mechanisms of 5-MeO-DMT, particularly the durability of its long-term effects. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.
Subject(s)
Hallucinogens , Mental Disorders , Mice , Animals , Psilocybin , Instinct , Methoxydimethyltryptamines/pharmacology , Mental Disorders/drug therapyABSTRACT
An orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF 1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.
Subject(s)
Aminopyridines/chemical synthesis , Antidepressive Agents/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Action Potentials/drug effects , Administration, Oral , Adrenocorticotropic Hormone/blood , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Cerebral Cortex/metabolism , Corticotropin-Releasing Hormone/pharmacology , Dogs , Fasting , Humans , Injections, Intravenous , Locus Coeruleus/physiology , Male , Pituitary Gland/metabolism , Postprandial Period , Radioligand Assay , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Structure-Activity RelationshipABSTRACT
A series of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active 5-HT7 receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT7. All ligands produced a decrease of adenylate cyclase activity, indicative of their inverse agonism. Additionally, computational studies with a set of 22 inverse agonists, including these novel inverse agonists and inverse agonists known from literature, resulted in a pharmacophore model and a CoMFA model (R2 = 0.97, SE = 0.18). Docking of inverse agonists at the binding site of a model of the helical parts of the 5-HT7 receptor, based on the alpha carbon template for 7-TM GPCRs, revealed interesting molecular interactions and a possible explanation for observed structure-activity relationships.
Subject(s)
Isoquinolines/chemical synthesis , Piperazines/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Sulfonamides/chemical synthesis , Adenylyl Cyclase Inhibitors , Animals , Binding Sites , Cell Line , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Ligands , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Quantitative Structure-Activity Relationship , Radioligand Assay , Rats , Receptors, Serotonin/chemistry , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
On the basis of a set of 20 diverse 5-HT(7) receptor agonists, the pharmacophore for 5-HT(7) receptor agonism was determined. Additionally two CoMFA models were developed, based on different alignments of the agonists. Both models show good correlations between experimental and predictive pK(i) values and show a high degree of similarity. The CoMFA fields were subsequently used to map the agonist binding site of the model of the 5-HT(7) receptor. Important roles in ligand binding are attributed to Asp162 of TM3 (interaction with a protonated nitrogen), and Thr244 of TM5 (interaction with a substituent at an aromatic moiety). Amino acid residues of the aromatic cluster of TM6 are hypothesized to play an important role in ligand binding as pi-pi stacking moieties. Agonists missing a hydrogen-bond-accepting moiety, but possessing an aromatic substituent instead, seem to bind the receptor with high affinity as well by occupying a lipophilic pocket hosted by residues of TM5 and TM6.
