Robert A. Lahti

[3H]U-69593 a highly selective ligand for the opioid κ receptor

The selective κ agonist U-50488 was recently discovered and characterized. In this study, the receptor binding properties of [3H]U-69593, an analog of U-50488, were characterized. [3H]U-69593 binds with high affinity (3 nM) to membranes prepared from guinea pig, mouse and rat brain. The number of κ binding sites comprise only 13%, 9% and 4% of the total opioid sites, respectively. The benzmorphans, dynorphin, and compounds structurally related to U-50488 have high affinity for this κ site.

Properties of a selective kappa agonist, U-50,488H

U-50,488H has been shown to be a naloxone antagonizable analgesic in rodents. However, the dose of naloxone needed for antagonism is higher than it is for morphine. U-50,488H does not produce physical dependence; however it does produce tolerance upon chronic administration. U-50,488H is cross tolerant with bremazocine but not with morphine. Monkeys trained to discriminate ethylketocyclazocine (EKC) from saline show a complete generalization to U-50,488H but not to morphine. The evaluation of U-50,488H in 3H-EKC site-selective binding indicated that U-50,488H has a high affinity for the kappa receptor (Ki = 114 nM) and a low affinity for the mu receptor (Ki = 6100 nM). The ratio of Ku/Kk was 0.08 for morphine, 0.4 for dynorphin, and 53.5 for U-50,488H. The data suggest that U-50,488H is a selective agonist at the opioid kappa receptor.

U-50488H, a pure kappa receptor agonist with spinal analgesic loci in the mouse

U-50,488H is a chemically novel analgesic that is a potent opioid-like agent on the mouse tail flick and electrically stimulated guinea pig ileum tests. U-50,488H is a very weak competitor for naloxone binding sites in brain and ileum. However, the drug has high affinity for kappa receptor binding sites revealed by competition for EKC sites in the presence of dihydromorphine. Morphine has both supraspinal and spinal sites of action since it was a potent analgesic after both intracranial and intraspinal injections. However, U-50,488H works predominantly at the spinal level. Dynorphin may be an endogenous ligand at this site. Studies on cat dorsal horn neurons suggest that U-50,488H analgesia may be due to an increase in threshold for neuron excitation.

The effect of minor tranquilizers on stress-induced increases in rat plasma corticosteroids

In this study a variety of psychoactive drugs were evaluated for their ability to block a stress-induced elevation in rat plasma corticosteroids. Stress was applied by placing the rats in different cages and moving them to a novel environment which resulted in a rapid increase in plasma corticosteroids, near maximal with 30 min, followed by a decrease to normal by 2 h. Meprobamate, phenobarbital, diazepam and several other benzodiazepines, all of which exhibit anxiolytic properties, were able to block the stress-induced increase. U-33,030 and U-31,889, two triazolobenzodiazepine derivatives, were the most potent compounds tested. No other type of psychoactive compound demonstrated this activity.

Structure-activity relationships of enkephalins containing serially replaced thiomethylene amide bond surrogates

An isomeric series of four leucine-enkephalin analogs containing the thiomethylene ether unit as an amide bond replacement in all positions have been prepared by solid phase methods. The resulting pseudopeptides divulged widely differing retentive behaviors on reversed phase high performance liquid chromatography (HPLC). An analog containing the Phe psi[CH2S]Leu dipeptide replacement at the 4-5 position exhibited binding close to the parent, leucine enkephalin; its guinea pig ileum (GPI) activity was the highest of the analogs tested. Another compound, Tyr psi[CH2S]Gly1-2]-Leu-enkephalin, also displaced 3H-etorphine well in the binding assay, but caused increased contractions in the GPI assay at low concentrations. The Phe psi[CH2S]Leu results are not compatible with the necessity of a beta-turn structure for agonist activity in the GPI assay.

Pharmacological profile of the antidepressant adinazolam, a triazolobenzodiazepine

Adinazolam, which is a 1-dimethylaminomethyl triazolobenzodiazepine, is an effective anxiolytic agent as defined by suppression of stress-induced increases in plasma corticosteroids. Adinazolam is also an effective antagonist of pentylenetetrazole. The 1-dimethylaminoethyl triazolo analog, U-43,465F, was inactive in the stressed rat test and only weakly active against pentylenetetrazole. Adinazolam and U-43,465F have been previously shown to have antidepressant activity in classical screening tests. They have also been found to potentiate the effect of norepinephrine and this is consistent with the activity of the known antidepressants; U-43,465F was found to be equieffective to imipramine in this test. Adinazolam was also effective; however, the magnitude of the potentiation was not as great. The uptake of norepinephrine was only weakly affected by either compound. Potentiation or uptake of serotonin were not significantly-altered pharmacological factors. Receptor binding studies were negative except at the benzodiazepine receptor. Chronic treatment with adinazolam did not decrease the number of beta-adrenergic receptors in the cerebral cortex of the rat, in contrast to the positive effect of imipramine. The discovery of triazolobenzodiazepines with antidepressant activity is of special interest. These agents will hopefully have lower toxicity than the tricyclic antidepressants and thus possess a more favourable therapeutic index. This would be advantageous in the treatment of depression.

Apomorphine antagonism of the elevation of homovanillic acid induced by antipsychotic drugs

Abstract Apomorphine was found to be effective in antagonizing the homovanillic acid elevating activity of several antipsychotic agents. Increasing doses of chlorpromazine overcame the effect of apomorphine on homovanillic acid and demonstrated the competitive nature of these drugs for the dopaminergic receptors. Several apomorphine-like compounds, and amantadine, did not exert the antagonistic effect displayed by apomorphine. The relationship of these effects to the production of extrapyramidal side effects and to antipsychotic activity is briefly discussed.

Autoradiographic Identification of Prolactin Binding Sites in Rat Median Eminence

Binding sites for prolactin were localized and quantified in the female rat brain by in vitro autoradiographic analysis with iodine-125-labeled ovine prolactin. Following incubation, labeled prolactin bound preferentially to the median eminence and choroid plexus of the lateral and third ventricles. The addition of excess unlabeled ovine prolactin blocked binding of the labeled hormone in the choroid plexus, and attenuated prolactin binding in the median eminence. These results provide evidence for median eminence. These results provide evidence for prolactin-specific recognition sites in the median eminence, a region intimately involved in the hypothalamic regulation of prolactin secretion.

Synthesis of metabolically stable arylpiperazine 5-HT1A receptor agonists

Abstract Although N-alkylarylpiperazines as a class are finding use as anxiolytics and antidepressants, many of these arylpiperazines are highly metabolically labile at the n-alkyl-piperazine bond. We have found that cyclopropanating the n-butyl chain contained in the 5-HT1A receptor agonist ipsapirone (2) instills a resistance to this metabolism as well as providing information about the geometrical requirements of the 5-HT1A receptor.

Comparative neuroanatomical distribution of the κ and μ opioid receptors in guinea pig brain sections

The opiate family of receptors is believed to consist of the mu, delta, kappa and sigma subtypes. Autoradiographic studies have been conducted to define the distribution of the mu and delta receptors. However, due to the lack of a selective ligand definitive studies have not been reported for the kappa receptor. Recently such a ligand was discovered and characterized. Results are presented in which the distribution of kappa receptors in guinea pig brain slices were determined using autoradiographic techniques and its distribution compared to that of a typical mu ligand. The results demonstrate numerous differences between the two opioid systems. The kappa receptors predominate in the prefrontal cortex, the nucleus accumbens, and deep cortex; whereas the mu receptors have a more intense, broader and different distribution.