Discriminative stimulus properties of α-ethyltryptamine (α-ET) in rats: α-ET-like effects of MDMA, MDA and aryl-monomethoxy substituted derivatives of α-ET.

Rationale α-ET (α-ethyltryptamine), a homolog of the classical hallucinogen α-methyltryptamine, was once prescribed clinically as an antidepressant. Classical psychedelic drugs are currently of interest as potential pharmacotherapy for psychiatric disorders. Objectives Drug discrimination was used to (a) determine if α-ET-like stimulus effects could be engendered by the prototypical phenylalkylamines MDMA ("Ecstasy") or MDA ("Love Drug") and (b) evaluate the α-ET-like stimulus effects of four synthesized aryl-substituted monomethoxy analogs of α-ET (4-OMe-, 5-OMe-, 6-OMe- and 7-OMe-α-ET).

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI, or DOX where X = -I) was first synthesized in 1973 in a structure-activity study to explore the effect of various aryl substituents on the then newly identified, and subsequently controlled, hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, or DOX where X = -CH). Over time, DOI was found to be a serotonin (5-HT) receptor agonist using various peripheral 5-HT receptor tissue assays and later, following the identification of multiple families of central 5-HT receptors, an agonist at 5-HT serotonin receptors in rat and, then, human brain. Today, , currently referred to as , are receiving considerable attention for their potential therapeutic application in various neuropsychiatric disorders including treatment-resistant depression.

Merging cultures and disciplines to create a drug discovery ecosystem at Virginia commonwealth university: Medicinal chemistry, structural biology, molecular and behavioral pharmacology and computational chemistry.

The Department of Medicinal Chemistry, together with the Institute for Structural Biology, Drug Discovery and Development, at Virginia Commonwealth University (VCU) has evolved, organically with quite a bit of bootstrapping, into a unique drug discovery ecosystem in response to the environment and culture of the university and the wider research enterprise. Each faculty member that joined the department and/or institute added a layer of expertise, technology and most importantly, innovation, that fertilized numerous collaborations within the University and with outside partners. Despite moderate institutional support with respect to a typical drug discovery enterprise, the VCU drug discovery ecosystem has built and maintained an impressive array of facilities and instrumentation for drug synthesis, drug characterization, biomolecular structural analysis and biophysical analysis, and pharmacological studies.

Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT and 5-HT serotonin receptors.

Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT (h5-HT) serotonin receptor agonists. Activation of a related receptor population, h5-HT receptors, has been demonstrated to result in adverse effects including cardiac valvulopathy. We previously published on the binding of several such agents at the two receptor subtypes.

Do 2-(Benzoyl)piperidines Represent a Novel Class of hDAT Reuptake Inhibitors?

2-(Benzoyl)piperidines (analogues of ), structural hybrids of the clinically employed ADHD medication methylphenidate () and the abused synthetic cathinone pentedrone (), have been previously reported to act as novel and selective reuptake inhibitors of the human dopamine transporter (hDAT). One of the more potent benzoylpiperidines, as is the case with methylphenidate analogues, is its 3,4-dichloroaryl counterpart. Here, we demonstrate using homology models that these compounds (i.

Medicinal chemistry: The key to critical thinking in pharmacotherapy.

Introduction: Medicinal chemistry is a polarizing subject for pharmacy students where, if not embraced, future pharmacists may be limited in their role as drug experts. An understanding of medicinal chemistry and its structure-activity relationships creates a strong foundation upon which our knowledge of pharmacotherapy is built.

Perspective: As the field of pharmacy has shifted to an increasingly clinical role, with an emphasis on patient care as a member of the interprofessional team, pharmacy has also seen an increase in postgraduate training, specifically residencies and fellowships.

Non-conserved residues dictate dopamine transporter selectivity for the potent synthetic cathinone and psychostimulant MDPV.

Clandestine chemists are currently exploiting the pyrrolidinophenone scaffold to develop new designer drugs that carry the risk of abuse and overdose. These drugs promote addiction through the rewarding effects of increased dopaminergic neurotransmission. 3,4-Methylenedioxypyrovalerone (MDPV) and its analogs are illicit psychostimulants of this class that are ∼50-fold more potent than cocaine at inhibiting the human dopamine transporter (hDAT).

Computational analysis of non-competitive antagonist arylguanidine-α7 nAChR complexes.

meta-Chlorophenylguanidine (1) is a non-competitive α7 nicotinic acetylcholine receptor (nAChR) antagonist. Here we examined the hydrogen bond donor role of the anilinic N-H on the inhibitory effect of 1 by preparing its N-CH counterpart 2. Analog 2 was found to be at least as potent as 1 as a non-competitive α7 nAChR antagonist in a patch-clamp assay.

NH- and N-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure-Activity Relationship Studies.

We previously reported that -(3-chlorophenyl)guanidine () represents a novel α7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure-activity relationship (SAR). Preliminary data suggested that the N-methyl analog of , , was several times more potent.

Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice.

Known classic psychedelic serotonin 2A receptor (5-HTR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HTR can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine.

X-Ray Crystal Structure of a 2-Amino-3,4-dihydroquinazoline 5-HT Serotonin Receptor Antagonist and Related Analogs.

Certain 2-amino-3,4-dihydroquinazolines bind at 5-HT serotonin receptors and act as antagonists (e.g. 6-chloro) whereas others bind with little to no affinity and lack functional activity (e.

Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test.

Rationale: 2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT serotonin receptor antagonist mechanism.

Revised Pharmacophore Model for 5-HT Receptor Antagonists Derived from the Atypical Antipsychotic Agent Risperidone.

Pharmacophore models for 5-HT receptor antagonists consist of two aromatic/hydrophobic regions at a given distance from a basic amine. We have previously shown that both aromatic/hydrophobic moieties are unnecessary for binding or antagonist action. Here, we deconstructed the 5-HT receptor antagonist/serotonin-dopamine antipsychotic agent risperidone into smaller structural segments that were tested for 5-HT receptor affinity and function.

"Methylene Bridge" to 5-HT Receptor Antagonists: Conformationally Constrained Phenylguanidines.

Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT receptors (e.g., partial agonist, agonist, superagonist).

des-Formylflustrabromine (dFBr): A Structure-Activity Study on Its Ability To Potentiate the Action of Acetylcholine at α4β2 Nicotinic Acetylcholine Receptors.

The naturally occurring indole alkaloid des-formylflustrabromine (dFBr; 1) is one of the first agents shown to act as a selective positive allosteric modulator (PAM) at α4β2 nicotinic acetylcholine receptors (nAChRs). We previously deconstructed this agent to determine which of its structural features contribute to its actions and have identified an agent that might serve as the basis for a " working pharmacophore". Here, we elaborate the dFBr (1; EC = 0.

A new chemotype inhibitor for the human organic cation transporter 3 (hOCT3).

Human organic cation transporters (OCTs) represent an understudied neurotransmitter uptake mechanism for which no selective agents have yet been identified. Several neurotransmitters (e.g.

Reevaluation of fenpropimorph as a σ receptor ligand: Structure-affinity relationship studies at human σ receptors.

Fenpropimorph (1) is considered a "super high-affinity" σ receptor ligand (K=0.005nM for guinea pig σ receptors). Here, we examine the binding of 1 and several of its deconstructed analogs at human σ (hσ) receptors.

Synthetic Cathinones: A Brief Overview of Overviews with Applications to the Forensic Sciences.

the fresh leaves of which (i.e., ) are used for their central stimulant actions, has been known for many hundreds of years.

Structure-Activity Relationships of Synthetic Cathinones.

Until recently, there was rather little interest in the structure-activity relationships (SARs) of cathinone analogs because so few agents were available and because they represented a relatively minor drug abuse problem. Most of the early SAR was formulated on the basis of behavioral (e.g.

Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT) Subunit A Receptors.

Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH group or a stronger electron withdrawing (i.e.

Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists.

Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction.

Receptor-ligand interaction at 5-HT3 serotonin receptors: a cluster approach.

A fundamental understanding of the interaction of ligands with biological receptors is important because many drugs exert their influence via receptors. Using a cluster approach, we have studied the role of structural and electronic parameters on receptor-ligand binding by carrying out density functional theory based calculations. As model systems, we have studied substituted arylguanidines, which activate 5-HT3 receptors in a manner similar to that of serotonin.

2-Amino-6-chloro-3,4-dihydroquinazoline: A novel 5-HT3 receptor antagonist with antidepressant character.

2-Amino-6-chloro-3,4-dihydroquinazoline HCl (A6CDQ, 4) binds at 5-HT3 serotonin receptors and displays antidepressant-like action in the mouse tail suspension test (TST). Empirically, 4 was demonstrated to be a 5-HT3 receptor antagonist (two-electrode voltage clamp recordings using frog oocytes; IC50=0.26μM), and one that should readily penetrate the blood-brain barrier (logP=1.

Deconstruction of the α4β2 nicotinic acetylcholine receptor positive allosteric modulator desformylflustrabromine.

Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using two-electrode voltage clamp techniques. Although the intact structure of 1 was found to be optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity.

Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships.

The 5-hydroxytryptamine (5-HT) 1E receptor is highly expressed in the human frontal cortex and hippocampus, and this distribution suggests the function of 5-HT(1E) receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT(1E) receptor gene, knockout strategies cannot be used to elucidate this receptor's functions.