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Biomedical subjects

J Szmuszkovicz

Publications and source records attributed to J Szmuszkovicz.

15 recordsLinked to original sources
PubMed1999

U-50,488 and the kappa receptor: a personalized account covering the period 1973 to 1990.

All clinically significant analgesics for severe pain derive from the morphine model. Morphine has provided a fertile area for medicinal chemistry research and received an additional stimulus in the 1970s with the appearance of the opioid receptors. The background for the birth of U-50,488 is described herein. It occurred before the discovery of the kappa receptor and, thus, U-50,488 was classified originally as a non-mu compound, and only later as a kappa agonist. U-50,488 provided a succinct template for structural modifications and they are described for the period up to 1990. A description of the structural classes of kappa agonists is provided including a summary of kappa recognition sites based on known agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Syntheses of benzoquinolizidine and benzoindolizidine derivatives as anti-amnesic agents.

Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine have been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research was undertaken to produce an acetylcholinesterase inhibitor by employing 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) as templates. Thus, we aimed to achieve three goals relative to tacrine: eliminate the pyridine and quinoline moieties and render the molecule less flat. Overall, the compounds we prepared were poorer inhibitors of acetylcholinesterase compared to tacrine. The single exception was compound 6f which exhibited an effect comparable to that of tacrine, but only at a dose of the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 6b, this compound proved to be an effective anti-amnesic agent at 45 mg/kg dose.

Animals↗
PubMed1999

Syntheses of 1,2-diamino and 1,2-aminoalcohol derivatives in the piperidine and pyrrolidine series as anti-amnesic agents.

Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine has been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research is a continuation of our efforts in the area of 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) (cf. ref9). A serendipitous discovery led us to the biologically active open chain analogue 9, and we proceeded to elaborate on this molecule. Overall, the compounds we prepared were poor inhibitors of acetylcholinesterase as compared to tacrine. The single exception was compound 20 which exhibited an effect comparable to that of tacrine, but only at a dose in the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 9, this compound was found to be an effective antiamnesic agent.

Alcohols↗
PubMed1999

U-50,488 and the kappa receptor. Part II: 1991-1998.

This review, Part II, follows an earlier article, Part I, published in volume 52 of this series. Part II is a discussion of centrally and peripherally acting kappa agonists which can be considered analogs of U-50,488. Included also are three classes of kappa agonists which fall outside of the scope of the general structure of U-50,488. These are benzodiazepines, phenothiazines and diazobicyclonanones. The discussion also covers other pertinent topics including labelled ligands and sigma receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Synthesis and biological activity of 2-amino-1-oxa-2,3-dihydro-1-H-phenalene derivatives.

The preparation of two 2-dialkylamino-1-oxa-2,3-dihydro-1H-phenalenes (3 and 4) is described. Lewis acid-catalyzed Baeyer-Villiger reaction of acenaphthenone (5) gave the lactone 6. Reduction afforded the lactol 7, which was reacted with amines to give the target compounds 3 and 4. Investigation of the effects of these compounds on catechol and indole metabolism revealed that they lack the dopamine antagonist or agonist and serotonin agonist properties of the respective deoxy analogues.

5-Hydroxytryptophan↗
PubMed1987

Isolation, identification and synthesis of a metabolite of tazadolene succinate.

Metabolism of tazadolene (1), a novel non-opioid analgesic with antidepressant properties, affords the 4-hydroxy and 3-methoxy-4-hydroxy derivatives (phenyl ring) of the drug, and N-[2-(phenylmethylene)cyclohexyl]-beta-alanine (4). The isolation, identification and synthesis of the latter metabolite is described.

Analgesics↗
PubMed1985

Factors affecting binding of trans-N-[2-(methylamino)cyclohexyl]benzamides at the primary morphine receptor.

In this paper, we describe the synthesis of a series of trans-N-[2-(methylamino)cyclohexyl]benzamides possessing morphine-like pharmacological properties. The affinity of the compounds for the agonist and antagonist states of the mu opioid receptor has been established by means of an in vitro binding assay. We have investigated the geometry and electronic structure of the molecules using molecular mechanics and an ab initio SCF-MO procedure with FSGO basis sets. Comparison to naloxone reveals properties of possible importance in receptor association. We have considered both the S,S and R,R isomers in the binding model. Statistical analyses imply that three factors play a significant role in binding: (1) membrane-water partitioning, (2) the capacity of the aromatic ring and amine N-substituent to act as electron acceptors, (3) the conformational energy required to attain the binding configuration.

Animals↗
PubMed1981

A new nontricyclic antidepressant agent. Synthesis and activity of N-[trans-2-(dimethylamino)cyclopentyl]-N-(3,4-dichlorophenyl)propanamide and related compounds.

A series of new nontricyclic antidepressant compounds was synthesized. A representative of this class is compound 6. Five structural parameters were investigated: ring size, cis/trans stereochemistry, amide substitution, aromatic substitution, and amine substitution. The pharmacological tests employed, indicative of antidepressant activity, were yohimbine potentiation test, oxotremorine antagonism test, and apomorphine potentiation test. Structure--activity relationship is discussed.

Animals↗