A Nadzan | PubMed Health

PubMed1998

Matrix metalloproteinase inhibitors: a structure-activity study.

Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.

Chromatography, High Pressure Liquid↗

PubMed1992

Evaluation of a stable CCK agonist (A68552) in conditioned avoidance responding in mice, rats, and primates: comparison with typical and atypical antipsychotics.

In a variety of in vivo and in vitro tests, cholecystokinin (CCK) has been shown to produce effects that would suggest a functional antagonism of dopamine. On that basis, it has been hypothesized that CCK could have antipsychotic effects. We compared the CCK agonist, A68552, to the antipsychotics haloperidol (HAL), clozapine (CLOZ) and sulpiride (SULP) in various forms of conditioned avoidance using rats, mice, and cynomolgus monkeys. In rats, HAL disrupted both acquisition of a conditioned shelf-jump avoidance response and performance of the response by previously trained animals. CLOZ and SULP were ineffective in suppressing performance by previously trained rats but blocked acquisition of the response. CLOZ disrupted avoidance responding on the first 3 of 4 consecutive days of acquisition. SULP significantly suppressed avoidance responding on the last 3 days and significantly increased escape failures on day 2. A68552 administered during acquisition failed to significantly suppress avoidance responding. In mice, both HAL and CLOZ blocked performance of two-way shuttle conditioned avoidance at doses (0.1 and 3.0 mg/kg, IP, respectively) that had no effect on escape responding. A68552 at doses up to 1.07 mg/kg IP had no effect on performance. Mice treated with A68552 during acquisition showed a mild but statistically significant suppression of avoidance and an equivalent suppression of escape responding. Cynomolgus monkeys trained in a conditioned avoidance procedure were sensitive to the disruptive effects of HAL at a dose of 0.03 mg/kg IM while A68552 was without significant effect at doses up to those producing emesis (0.214 mg/kg, IM). A68552 does not resemble either HAL or the "atypical" antipsychotics, CLOZ or SULP, in conditioned avoidance tests.

Animals↗