Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles.

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated.

Behavioral sensitization, behavioral tolerance, and increased [3H]WIN 35,428 binding in rabbit caudate nucleus after repeated injections of cocaine.

This study examined whether changes in the behavioral response to repeated intravenous injections of cocaine hydrochloride (4 mg/kg, twice daily for 22 days) might be related to alterations in the dopamine (DA) transporter as measured by the binding of the potent cocaine analog [3H]WIN 35,428 to membranes derived from fresh caudate tissue. Rabbits demonstrated both tolerance and sensitization. Tolerance occurred for cocaine elicited convulsions, whereas sensitization occurred to the ability of cocaine to elicit motor activity, facial twitches, and head bobbing.

[3H]WIN 35,428 binding in the caudate nucleus of the rabbit: evidence for a single site on the dopamine transporter.

The binding of the potent cocaine analog, WIN 35,428 ((-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-napthalenedisulfonate), was investigated in adult Dutch Belted rabbits by using membrane fractions prepared from fresh caudate nucleus. The consistent finding of this study was that [3H]WIN 35,428 binds to a single class of sites. For example: 1) kinetic analysis revealed that the rate of association and dissociation of [3H]WIN 35,428 was linear; 2) analyses of saturation experiments or homotopic displacement with cold WIN 35,428 by three separate methods statistically favored a one-site model; and 3) heterotropic displacement with drugs that bind to the dopamine (DA) transporter consistently yielded only a single class of binding sites as reflected by a complete displacement of [3H]WIN 35,428 and Hill slopes of approximately 1 (range, 0.

The low affinity binding site for the cocaine analog, WIN 35,428 is an artifact of freezing caudate tissue.

Binding of the cocaine analog [3H] WIN 35,428 was investigated in rat and rabbit caudate. In membranes prepared from fresh tissue, [3H] WIN 35,428 binding was characterized by a single high affinity site with a Kd of 2.5 nM for the rabbit and 5.