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M K Scott

Publications and source records attributed to M K Scott.

31 records · Page 2Linked to original sources
PubMed1992

Pyrrole mannich bases as potential antipsychotic agents.

Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.

Animals↗
PubMed1991

Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TIBO) derivatives.

A series of 6-substituted 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-ones (9) have been synthesized and tested for their ability to inhibit the replication of the HIV-1 virus in MT-4 cells. Two synthetic methods are described, one of which allows the synthesis of single enantiomers of the final products. A structure-activity study was done within the series of compounds to determine the optimum group for the 6-position substitution and to determine whether the activity was enantiospecific at the 5-position, which was substituted with a methyl group. The best analogue, 9jj, inhibited HIV-1 with an IC50 of 4 microM, which is comparable to the activity level of DDI, a 2',3'-dideoxynucleoside-type structure undergoing clinical trials as an anti-AIDS therapy.

Antiviral Agents↗
PubMed1989

Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.

Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.

Animals↗
PubMed1988

Block of conditioned avoidance responding in the rat by substituted phenylpiperazines.

Ortho-methoxyphenylpiperazine (OMPP) and meta-substituted chlorophenylpiperazine (MCPP) blocked conditioned avoidance responding (CAR) in the rat (ED50 values = 5.6 (4.6, 7.3) and 2.4 (1.9, 2.9) mg/kg i.p. (95% confidence limits), respectively) without markedly altering escape responding. Since this test predicts antipsychotic efficacy, the piperazines were examined in radioligand binding assays and found to have no affinity for dopamine (DA) binding sites, but were active at serotonin binding sites. OMPP displaced ligands for the 5-HT1A binding site with high affinity (Ki = 9.5 (5.4, 17.9) nM) but was inactive at 5-HT2 sites (Ki greater than 1000 nM). MCPP, on the other hand, displaced ligands for 5-HT1, 5-HT1A and 5-HT2 binding sites with similar potencies (Ki values = 25 (3, 67), 23 (14, 40) and 40 (33, 48) nM, respectively). Pretreatment with metergoline (1.0 mg/kg i.p. -30 min) reduced MCPP- but not OMPP-induced block of CAR. OMPP, on the other hand, acted as a DA receptor antagonist in vivo blocking amphetamine-induced stereotyped behavior, whereas MCPP did not. Neither produced catalepsy even given in doses 8-10 times those required to block CAR. Insofar as these compounds lack antidopaminergic activity in vivo, yet are active in a test (CAR) predictive of antipsychotic activity in which DA receptor antagonists are active, they may be novel antipsychotic agents, or, perhaps, false positives in the CAR paradigm.

Amphetamine↗
PubMed1987

Antisecretory activity of human, dog, and rat metabolites of fenoctimine.

Fenoctimine (1a), a nonanticholinergic inhibitor of gastric acid secretion in dogs and rats, was evaluated as a gastric antisecretory agent in humans. In humans it exhibited weak antisecretory activity and caused anticholinergic-like side effects such as dry mouth and nasal passages. Studies of the metabolic fate of fenoctimine in humans, dogs, and rats provided structures of the resultant metabolites. These were synthesized and tested for antisecretory and anticholinergic activity. The human metabolites were all less active than fenoctimine as antisecretory agents, and some displayed significant anticholinergic activity. These results suggest that the unexpectedly weak effect of fenoctimine as a gastric antisecretory agent in humans, as well as anticholinergic effects, may be due to its extensive metabolism, which is different from that seen in dog and rat.

Animals↗
PubMed1983

4-(Diphenylmethyl)-1-[(imino)methyl]piperidines as gastric antisecretory agents.

4-(Diphenylmethyl)-1-piperidinemethanimine (1) is a potent oral gastric antisecretory agent in rats but contains a strong anticholinergic component. Since a nonanticholinergic gastric antisecretory drug would be useful in the treatment of peptic ulcer disease, a program was initiated by us to find such an agent based on 1. Compound 1 contains structural elements common to the anticholinergics atropine and homatropine. Studies on the structure-activity relationships of these compounds and their derivatives have revealed certain modifications that diminish or abolish anticholinergic activity. The application of these modifications to the design of analogues of 1 afforded an antisecretory compound, 4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine (3h, fenoctimine), which exhibited no anticholinergic activity. Fenoctimine is undergoing clinical trial as a gastric antisecretory drug.

Animals↗
PubMedDate not supplied

Effects of dialysis membrane on intradialytic vancomycin administration.

STUDY OBJECTIVE: To quantify the influence of hemodialyzers on vancomycin removal when the drug was infused during hemodialysis. DESIGN: Prospective, controlled, crossover study with three arms. SETTING: A university-affiliated medical center. PATIENTS: Eight subjects receiving outpatient hemodialysis. INTERVENTIONS: The three treatment arms were vancomycin 1000 mg infused after dialysis was completed (control), and the same dosages infused during the last hour of hemodialysis with a cellulose triacetate (CT) and a cellulose acetate (CA) hemodialyzer. MEASUREMENTS AND MAIN RESULTS: The areas under the curve from time zero to 44 hours (AUC0-44 hrs) for the three study arms were significantly different (p < 0.05), with the mean vancomycin AUC0-44 hrs being significantly lower when administered during CT and CA dialysis (73.7% and 87.2% of control; p < 0.05 vs control). The mean vancomycin peak concentration achieved during CT dialysis was significantly lower than for the CA and control arms (20.5, 23.9, 27.0 mg/L, respectively). Forty-four-hour postinfusion concentrations were similarly lower. CONCLUSION: Clinicians should recognize that the composition of the hemodialyzer significantly influences vancomycin serum concentrations when the drug is administered during hemodialysis.

Anti-Bacterial Agents↗