title: Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism.
abstract: Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.
authors.affiliation: Discovery Neuroscience, Wyeth Research, Princeton, NJ 08543-8000, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Platt
authors.forename: Stacey J Sukoff
authors.initials: SJ
authors.lastname: Rizzo
authors.forename: Claudine M
authors.initials: CM
authors.lastname: Pulicicchio
authors.forename: Caitlin
authors.initials: C
authors.lastname: Wantuch
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Zhang
authors.forename: Terri
authors.initials: T
authors.lastname: Cummons
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.forename: Corey N
authors.initials: CN
authors.lastname: Bender
authors.forename: Jean
authors.initials: J
authors.lastname: Zhang
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: Shendi
authors.initials: S
authors.lastname: Lu
authors.forename: S Johannes R
authors.initials: SJ
authors.lastname: Rajarao
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Smith
authors.forename: Adam D
authors.initials: AD
authors.lastname: Shilling
authors.forename: Jianyao
authors.initials: J
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Butera
authors.forename: Lynn
authors.initials: L
authors.lastname: Resnick
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Lee E
authors.initials: LE
authors.lastname: Schechter
authors.forename: Chad E
authors.initials: CE
authors.lastname: Beyer
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D054833:Isoindoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017551:Microdialysis; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013550:Swimming; D013894:Thirst / Q000187:drug effects
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D007093:Imidazoles; D054833:Isoindoles; D018341:Receptors, Adrenergic, alpha-2; C072125:BRL 44408