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Biomedical subjects

D Ignar

Publications and source records attributed to D Ignar.

4 recordsLinked to original sources
PubMed1999

Constitutive receptor systems for drug discovery.

This paper discusses the use of constitutively active G-protein-coupled receptor systems for drug discovery. Specifically, the ternary complex model is used to define the two major theoretical advantages of constitutive receptor screening-namely, the ability to detect antagonists as well as agonists directly and the fact that constitutive systems are more sensitive to agonists. In experimental studies, transient transfection of Chinese hamster ovary cyclic AMP response element (CRE) luciferase reporter cells with cDNA for human parathyroid hormone receptor, glucagon receptor, and glucagon-like peptide (GLP-1) receptor showed cDNA concentration-dependent constitutive activity with parathyroid hormone (PTH-1) and glucagon. In contrast, no constitutive activity was observed for GLP-1 receptor, yet responses to GLP-1 indicated that receptor expression had taken place. In another functional system, Xenopus laevi melanophores transfected with cDNA for human calcitonin receptor showed constitutive activity. Nine ligands for the calcitonin receptor either increased or decreased constitutive activity in this assay. The sensitivity of the system to human calcitonin increased with increasing constitutive activity. These data indicate that, for those receptors which naturally produce constitutive activity, screening in this mode could be advantageous over other methods.

Animals↗
PubMed1991

Endocrine function as a target of perinatal drug effects: methodologic issues.

The goal of this chapter is to indicate potential endocrine targets of perinatal drug exposure, to describe the methodologic issues involved in detecting changes in hormone secretion, and to provide examples of several endocrine systems in which exposure to drugs during development significantly impaired normal endocrine development. Finally, we attempted to show that endocrine function is both a target and useful marker for detecting effects of drug of abuse on development that provides the advantages of accurate quantitation and relative response stability across ontogeny.

Animals↗
PubMed1987

Endocrine consequences of perinatal methadone exposure.

In summary, we have shown that marked acute responses as well as persistent changes in hypothalamopituitary responsivity to opiate challenge result from perinatal opioid addiction. We have also shown that different endocrine systems and opioid receptor subtypes develop at different rates, and that the responses of these systems depend upon the relative timing of the treatment regimen and the functional development of the particular opioid system involved. It should be emphasized that these studies have investigated only a single developmental window. The additional critical question of how opioid neuron function is affected by treatment during the period of active neuronal differentiation has not yet been answered. However, these studies do demonstrate the utility of this neuroendocrine model in assessing opioid function following chronic treatment regimens. By using neuroendocrine function as an end point, multiple systems can be studied simultaneously in the same animal. This has a particular advantage in studying the effects of chronic drug exposure on the developing nervous system, because hormone secretion is an easily quantifiable and early maturing functional index which can be used to identify vulnerable (and resistant) systems. Endogenous opioid systems appear to be particularly important in neuroendocrine regulation during the early phase of development, when other neural controls have not yet matured. Our preliminary results suggest that specific opioid systems that mature early may be especially important in the specific neuroendocrine effects of perinatal opiate addiction.

Aging↗