Biomedical subjects

S Y Ablordeppey

Publications and source records attributed to S Y Ablordeppey.

9 recordsLinked to original sources

PubMed2000

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.

Animals↗

PubMed1999

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.

Alkaloids↗

PubMed1999

Systemic antifungal agents against AIDS-related opportunistic infections: current status and emerging drugs in development.

No effective drug was available for the treatment of systemic fungal infections until the discovery of Amphotericin B in 1953. Since then flucytosine, azoles and later the triazoles, have now become available. The current interest in the development of new antifungal agents can partially be explained by the dramatic rise in the number of AIDS cases and the subsequent suppression of the immune system in patients with the disease. For example, over 90% of those diagnosed to be HIV-positive contract a fungal infection during the course of their illness. Other conditions that have spurred the development of new systemic antifungal agents include the increase in the frequency of bone marrow and organ transplants, the use of antineoplastic agents, long-term use of corticosteroids and even the indiscriminate use of antibiotics. The emergence of fungi resistant to currently available agents, especially the azoles, has made the need for new and effective antifungal agents more urgent. This review article focuses on agents targeted against opportunistic fungal infections, i.e., fungal infections which, in contrast to immunocompetent individuals, may cause serious life-threatening illness in immunocompromised individuals. Agents currently on the market or undergoing clinical development, as well as potential new agents that have been discovered, are discussed.

AIDS-Related Opportunistic Infections↗

PubMed1994

Structural features important for sigma 1 receptor binding.

Two problems that have hampered sigma receptor research are (i) a lack of high-affinity agents and (ii) the recent identification of multiple populations of sigma receptors (i.e., sigma 1 and sigma 2 sites). Recently, several high-affinity sigma ligands have been identified, and the term superpotent sigma ligands has been coined to describe agents with Ki values of < 1 nM. We have previously shown that appropriately N-substituted phenylalkylamines bind at sigma receptors with high affinity. In the present investigation, we examine the structure-affinity relationships of these phenylalkylamine derivatives for sigma 1 binding and describe some of the first superpotent sigma 1 ligands. A binding model was developed to account for the structural features of the phenylalkylamines that appear to be important for the interaction of these agents with sigma 1 sites.

Alkylation↗

PubMed1993

Detection of a neurotoxic quaternary pyridinium metabolite in the liver of haloperidol-treated rats.

Various theories have been proposed in the past to explain the side effects associated with haloperidol treatment. In this study, we tested the hypothesis that in vivo biotransformation of haloperidol to a quaternary pyridinium metabolite might contribute to some of these effects. Administration of haloperidol (IP or by gavage) to male Wistar rats results in its biotransformation to a butyrophenone quaternary pyridinium metabolite similar to MPTP metabolism to MPP+. The corresponding methyl quaternary pyridinium compound was not detected in the liver or brain of the rats used in this study. The proposed methyl quaternary pyridinium compound and the observed butyrophenone metabolite were tested for neurotoxicity in a frog model of MPTP action and were found to have neurotoxic effects, although the methyl quaternary pyridinium compound was much more toxic.

1-Methyl-4-phenylpyridinium↗

PubMed1993

The mechanism(s) of the antiaggregatory effects of cryptolepine: the role of cyclic adenosine monophosphate and cellular Ca2+.

1. In this investigation, the properties and possible mechanisms of the antiaggregatory effects of cryptolepine were evaluated. 2. Cryptolepine had no effect on platelet shape change but inhibited aggregation in a time-dependent manner. The inhibition of aggregation lacks agonist specificity, the IC50 values (x 10(-5) M) being 2.79 +/- 0.7 ADP 3.05 +/- 0.2 (U46619), 2.89 +/- 0.6 (A23187), 2.41 +/- 0.6 (thrombin), 4.05 +/- 0.9 (arachidonic acid) and 47.3 +/- 3.9 (PAF). 3. The antiaggregatory effects were fully reversible and surmountable at concentrations < or = 75 microM but unsurmountable at concentrations > or = 100 microM. 4. The coincubation of cryptolepine (25 and 50 microM) with cpt-cAMP (50 microM) resulted in increased inhibition of aggregation from 24.2 +/- 2.1% (25 microM) and 45.1 +/- 3.4% (50 microM) to 69.5 +/- 5.8% and 84.2 +/- 6.4%, respectively. 5. Cryptolepine (10 microM) synergized with stimulants of platelet adenylate cyclase, prostacyclin (0.5 and 1 nM) and forskolin (2.5 and 5 microM) to inhibit aggregation induced by adenosine diphosphate (ADP). The inhibition of aggregation by cryptolepine (10 microM; 18.2 +/- 1.5%) or prostacyclin (0.5 nM; 23.4 +/- 2.0%) increased to 62.6 +/- 3.8% (P < 0.01) on combined administration. 6. Following pretreatment with IBMX (50 microM), a phosphodiesterase (PDE) inhibitor, the inhibitory effect of cryptolepine (25 microM) increased from 21.5 +/- 2.1% to 42.3 +/- 3.7% (P < 0.01). In the presence of imidazole (2.5 mM), an activator of PDE, the inhibitory effects of cryptolepine reduced from 63.2 +/- 5.4% (50 microM) and 84.7 +/- 4.4% (75 microM) to 1.4 +/- 0.2% and 21.3 +/- 2.4%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1993

Effects of cryptolepine on collagen-induced aggregation and on the mobilization and metabolism of arachidonic acid by rabbit platelets.

1. We examined the effect of cryptolepine on collagen-induced aggregation and on the mobilization, and metabolism of arachidonic acid in rabbit platelets. 2. Preincubation of platelets with cryptolepine (50-100 microM) did not affect the primary wave of aggregation but resulted in a dose-dependent, surmountable inhibition of the secondary wave of aggregation induced by collagen (5 micrograms/ml). The inhibition by cryptolepine was greater when cryptolepine was incubated with the platelets after the peak of the primary wave of aggregation. 3. Cryptolepine (50-100 microM) dose-dependently inhibited thrombin (1.5 U/ml) and A23187 (2.5 microM)-induced release of 14C[AA] from platelet membrane phospholipid pools. The percentage inhibition of A23187-induced 14C[AA] release was 31.3 +/- 4.3% (50 microM) and 79.3 +/- 5.4% (100 microM), while thrombin-induced release was inhibited by 39.2 +/- 2.4% (50 microM) and 68.2 +/- 3.6% (100 microM). 4. At near maximal concentration (100 microM) which significantly inhibited secondary aggregatory response and 14C[AA] release, cryptolepine had no effect on the platelet metabolism of 14C[AA] to thromboxane B2, HHT and 12 HETE. 5. The present findings suggest that cryptolepine inhibited collagen-induced secondary aggregation through a selective antiphospholipase-like activity. There was no effect on platelet cyclooxygenase and lipoxygenase activities of platelets.

Alkaloids↗

PubMed1992

Freezing action of a metabolite of haloperidol in frogs.

In vivo metabolism studies led to the identification of a previously proposed metabolite of haloperidol, 4-(4'-chlorophenyl)-4-piperidinol (CPPO), in the liver of a haloperidol-treated rat. However, the secondary metabolites of CPPO that we have proposed were not observed in this study. Neurotoxicity studies in frogs, which have been used to detect N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action, showed that CPPO did not mimic the neurotoxicity of MPTP but caused a delayed and persistent freezing action in Rana pipiens frogs. It is proposed that this action may contribute to some of the delayed side-effects associated with haloperidol therapy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1985

Radioiodination and preliminary in vivo investigation of the alkaloid cryptolepine.

In this paper we report the successful labelling of cryptolepine with 131I using the chloramine T method. Quality control by ITLC of the labelled product showed 80% labelling but when the mixture was equilibrated with some amberlite (Cl-) anion resin to exchange the excess free iodide, the radiochemical purity was raised to greater than 90%. Preliminary biodistribution in a rat did not show specific localisation of the tracer; rather, rapid clearance from the blood was indicated. It appears that its main excretory pathway is the hepatobiliary tract despite its relatively small molecular weight of 365. Also, despite i.v. administration, an appreciable 8% uptake was found in the stomach at 1 h post injection, indicating the process of enterohepatic reflux. These findings may have some bearings on the antimicrobial property of the plant.

Adrenergic alpha-Antagonists↗