Jason E. Savage

N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists

N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.

In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs

HeadingAbstractn Rationale.Hypericum perforatum L. (St. Johns wort; SJW) is one of the leading psychotherapeutic phytomedicines and great effort has been devoted to clarifying its mechanism of action.n Objective. We have undertaken a comprehensive analysis of several pure compounds isolated from the crude extract to gain further insight into the molecular actions of various substituents of SJW.n Methods. We characterized the in vitro pharmacology of the naphthodianthrones hypericin and pseudohypericin, the phloroglucinol derivative hyperforin, and several flavonoids at 42xa0biogenic amine receptors and transporters using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program.n Results. The biflavonoid amentoflavone significantly inhibited binding at serotonin (5-HT1D, 5-HT2C), D3-dopamine, δ-opiate, and benzodiazepine receptors. The naphthodianthrone hypericin had significant activity at D3- and D4-dopamine receptors and β-adrenergic receptors. With the exception of the D1-dopamine receptor, the phloroglucinol derivative hyperforin was less active than other SJW constituents tested on all screened receptors.n Conclusion. Our present in vitro data clearly show that several pure substances in SJW are potential CNS psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner. Our data also reveal novel and heretofore unexpected interactions of pure compounds in SJW at a number of GPCRs, transporters, and ion channels. We hypothesize that additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW. These results and this general approach may impact our understanding of phytomedicines in general and H. perforatum specifically.

Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth.

In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.

Influence of chain length and N-alkylation on the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene.

Comparison of the serotonin 5-HT2A receptor affinities of chain lengthened and N-alkylated analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine imipramine suggests that the two agents bind to the receptor in different fashions. The demonstration that AMDA is highly selective for serotonin receptors (5-HT2A, K = 20nM; 5-HT2C, Ki=43nM) versus the dopamine D2 receptor (Ki>10,000nM), as well as the serotonin and norepinephrine transporters (Ki>10,000nM) further suggests that AMDA and the nonselective ligand imipramine interact with these target macromolecules in different ways.

9-(Aminomethyl)-9,10-dihydroanthracene is a novel and unlikely 5-HT2A receptor antagonist.

Structural elaboration of phenylethylamine to 9-(aminomethyl)-9,10-dihydroanthracene (AMDA) produces an agent with high affinity (Ki = 9.5-21 nM) at 5-HT2A receptors. It was shown that AMDA acts as a 5-HT2A receptor antagonist. The structure and molecular geometry of AMDA are not consistent with existing pharmacophore models for 5-HT2A receptor antagonist activity. Thus, AMDA may be a structurally novel parent of a new class of 5-HT2A receptor antagonists that binds to the receptor in a unique fashion that is distinct from the binding topology of existing 5-HT2A receptor antagonists.

The in vitro pharmacology of the β-adrenergic receptor pet ligand (s)-fluorocarazolol reveals high affinity for cloned β-adrenergic receptors and moderate affinity for the human 5-HT1A receptor

Abstract. Rationale: s-Fluorocarazolol [(S)-FCZ] is the major positron emission tomography (PET) ligand currently used to visualize central β-adrenergic receptors in vivo, although its pharmacology is incompletely known. Objective: Our objective was to comprehensively characterize the in vitro pharmacology of (S)- and (R)-FCZ to determine its suitability for study of central and peripheral β-adrenergic receptors. Methods: We characterized the in vitro pharmacology of (S)-FCZ at 42 biogenic amine receptors and transporters in vitro using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. Results: As expected (R)- and (S)-FCZ had high affinities for β-adrenergic receptors (Ki values=0.08–0.45xa0nM) and negligible affinities (Ki values>100xa0nM) for nearly all other tested receptors and transporters with the exception of the h5-HT1A receptor for which (S)-FCZ had high affinity (Ki=34xa0nM). Interestingly, (R)-FCZ had low affinity for the h5-HT1A receptor (Ki=342xa0nM). Conclusion: The high affinity of (S)-FCZ for the h5-HT1A receptor is not likely to interfere with studies of peripheral β-adrenergic receptors, since 5-HT1A receptors are expressed at very low levels outside the central nervous system. Indeed, computer simulations predict that even at low ligand concentrations, 5-HT1A binding in brain regions like hippocampus are likely to be substantial. Thus, (S)-FCZ may not be a suitable PET ligand for studies of central nervous system β-adrenergic receptors unless the contribution by 5-HT1A sites can be shown to be negligible.

Exploring the relationship between binding modes of 9-(aminomethyl)-9,10-dihydroanthracene and cyproheptadine analogues at the 5-HT2A serotonin receptor.

Comparison of the serotonin 5-HT2A receptor affinities of a parallel series of structural analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine cyproheptadine suggests that the two agents bind to the receptor in different fashions. Examination of ligand-receptor model complexes supports the experimental data and suggests a potential origin for the differences in binding modes.

Synthesis of potent and selective dopamine D4 antagonists as candidate radioligands

A series of dopamine D(4) antagonists was synthesized and evaluated as potential candidates for development as positron emission tomography (PET) radioligands. All new compounds display high affinity and selectivity for the D(4) receptors and compounds 5b, 5d, and 5e were identified as candidates for radioligand development.