Sedative/hypnotic, anesthetic-sparing, analgesic, and sympatholytic are produced through the activation of the a2A adrenoceptor subtype located in discrete CNS loci. Undesirable hypertension may occur at higher plasma concentrations of non selective a2 agonist through a2B adrenoceptor-mediated vasoconstriction. The investigators will determine whether the administration of nicardipine, an L-type Ca2+ channel blocker, can attenuate the vasoconstriction produced by dexmedetomidine and enhancing anesthesia/analgesia properties. These clinical studies will establish the utility of a """"""""functionally-selective"""""""" a2A agonist and provide the impetus for target-based drug design. To be able to model the structure of the human a2A adrenoceptor subtype as a target for drug design, the investigators will define the amino acid residues that confer subtype-selective binding, determine the alignment of the seven transmembrane domains, and validate the use of a structurally-defined analogous protein, bacteriorhodopsin, as a """"""""scaffold"""""""" on which to drape the receptors sequence. These in vitro studies will use recombinant DNA technology, coupled to molecular modeling. The investigators will also determine which a adrenoceptor subtype(s) mediate the enhanced efficacy of a2 agonists in an animal model of neuropathic pain. These studies will lead to the more effective use of existing drugs and the design of novel chemical entities for clinical development.
| Takada, Koji; Clark, David J; Davies, M Frances et al. (2002) Meperidine exerts agonist activity at the alpha(2B)-adrenoceptor subtype. Anesthesiology 96:1420-6 |
| Davies, M F; Reid, K; Guo, T Z et al. (2001) Sedative but not analgesic alpha2 agonist tolerance is blocked by NMDA receptor and nitric oxide synthase inhibitors. Anesthesiology 95:184-91 |
| Doze, V A; Chen, B X; Tinklenberg, J A et al. (1990) Pertussis toxin and 4-aminopyridine differentially affect the hypnotic-anesthetic action of dexmedetomidine and pentobarbital. Anesthesiology 73:304-7 |
| Doze, V A; Chen, B X; Maze, M (1989) Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. Anesthesiology 71:75-9 |
| Segal, I S; Vickery, R G; Walton, J K et al. (1988) Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha 2 adrenergic receptor. Anesthesiology 69:818-23 |
