Seth Y. Ablordeppey

Is a nitrogen atom an important pharmacophoric element in sigma ligand binding

A lingering question in sigma receptor ligand development is whether a nitrogen atom serves as an important pharmacophoric element in binding affinity. To address this question, we have synthesized several phenylalkylpiperidines and phenylalkylpiperazines and demonstrated that removal of the N atom from a typical phenylalkylpiperidine led to little or no binding to sigma receptors. In addition, where two N atoms occur in a compound, such as with phenylalkylpiperazines, the N atom on the longer alkyl chain appears to be more important. Thus, based on this study, the N atom is an important pharmacophoric element in the binding of phenylalkylpiperidines and phenylalkylpiperazines to sigma receptors.

Probing the proposed phenyl-A region of the sigma-1 receptor.

The proposed phenyl-A region of sigma (sigma) receptors accommodates several structural features. In this study we explored the possibility that appropriate structural features located at the phenyl-A region of sigma receptor sites could lead to more potent and selective agents for the sigma receptor subtypes. By keeping the phenyl-B substituent as the optimum omega-phenylpentyl moiety, and varying substituents in the phenyl-A region, we have observed changes in binding potency and selectivity at the sigma receptor subtypes. SAR for the binding of these compounds at sigma-2 sites was also examined.

Substituted Indoloquinolines as New Antifungal Agents

Cryptolepine (2) possesses desirable properties to serve as a lead in developing new antifungal agents. Using SAR techniques, several analogues of cryptolepine were designed to increase potency and to broaden the antifungal spectrum over several opportunistic microorganisms. A number of 2-substituted indoloquinolines have been synthesized and evaluated in antifungal screens and several have been shown to increase potency and expand the antifungal spectrum of cryptolepine. Comparison of MICs of a number of these analogues with standard antifungal agents, shows them to be comparable to Amphotericin B and Ketoconazole.

Probing the N-5 Region of the Indoloquinoline Alkaloid, Cryptolepine for Anticryptococcal Activity

N-5 Alkylated analogues of cryptolepine were synthesized and tested for anticryptococcal activity. Evidence provided in this study suggests that the active form of cryptolepine consists of the flat tetracyclic aromatic ring with the methyl group on the N-5 atom. It was also found that changes in the electronic density around the N-5 atom do not appear to affect activity. Steric hindrance of the N-5 substituents seems to decrease activity. Through systematic modification of the N-5 alkyl groups, o-phenylpentyl group was shown to possess the highest potency thus far.

Indolo[3,2-b]quinolines: Synthesis, Biological Evaluation and Structure Activity-Relationships

The tetracyclic indolo[3,2-b]quinoline ring system constitutes an important structural moiety in natural products exhibiting numerous biological activities. In particular, indolo [3, 2-b]quinoline, commonly known as linear quindoline is of particular interest, because of its rigid structure and scope of derivatization. Although the core linear quindoline skeleton shows little or no activity in several biological systems, introduction of a methyl group on the N-5 atom leading to cryptolepine induces remarkable activity against a broad spectrum of biological targets. A number of analogs of quindoline and cryptolepine have been synthesized, incorporating various functional groups on the core quindoline skeleton leading to improved biological activities. In this review, we describe various synthetic methodologies leading to the quindoline scaffold, the biological activities and the structure activity relationships (SAR) of quindoline derivatives toward different disease states to give a better picture of the importance of this moiety in medicinal chemistry.

Identification of A Butyrophenone Analog as a Potential Atypical Antipsychotic Agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one

The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.

Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens.

Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.

A CoMFA investigation of sigma receptor binding affinity: Reexamination of a spurious sigma ligand

Abstract A comparative molecular field analysis (CoMFA) investigation was conducted on the binding of 64 compounds to σ 1 receptors. Although CoMFA accurately predicted the binding affinities of the 64 compounds in the final set ( R 2 = 0.989 ), it was unable to predict the high affinity of the previously reported bridged σ ligand SC-50691. SC-50691, and its endo and exo isomers were synthesized and found to bind with much lower affinity than was previously reported.

Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

The synthesis and evaluation of several benzothiazole-based compounds are described in an attempt to identify novel dual-acting 5HT(1A) receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT(1A) receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT(1A) receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT(2C) receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side effects.

Isoquinuclidines: A Review of Chemical and Pharmacological Properties

Abstract The presence of the isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system in natural products displaying interesting pharmacological properties (such as ibogaine and dioscorine) has interested chemists and medicinal chemists for decades. This ring system may be viewed as a semi-rigid boat form of the piperidine ring and, when properly substituted, as a scaffold for rigid analogs of biologically active ethanolamines and propanolamines. Many pharmacologically active compounds based on the isoquinuclidine system have been synthesized utilizing standard or combinatorial chemistry techniques and diversity oriented synthetic routes have led to interesting derivatives which will be reviewed here.