title: Characterization of in vivo brain muscarinic acetylcholine receptor subtype selectivity by competition studies against (R,S)-[125I]IQNB.
abstract: We have studied the in vivo rat brain muscarinic acetylcholine receptor (mAChR) m2 subtype selectivities of three quinuclidine derivatives: (R)-3-quinuclidinyl benzilate (QNB), E-(+,+)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-(+,+)-IQNP), and E-(+,-)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-(+,-)-IQNP), and two tricyclic ring compounds: 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]-10,11-dihydro-5H-dibenz o [b,e][1,4]diazepin-11-one [sequence: see text] (DIBD) and 11-[[4-[4-(diisobutylamino)butyl-1-phenyl]acetyl]-5,11-dihydro-6H- pyrido [2,3-b][1,4]benzodiazepin-6-one [sequence: see text] (PBID), by correlating the regional inhibition of (R,S)-[125I]IQNB with the regional composition of the m1-m4 subtypes. Subtle effects are demonstrated after reduction of the between-animal variability by normalization to corpus striatum. Substantial in vivo m2-selectivity is exhibited by QNB and DIBD, modest in vivo m2-selectivity is exhibited by E-(+,+)-IQNP, and little or no in vivo m2-selectivity is exhibited by PBID and E-(+,-)-IQNP. Surprisingly, the in vivo m2-selectivity is not correlated with the in vitro m2-selectivity. For example, QNB, which appears to be the most strongly in vivo m2-selective compound, exhibits negligible in vitro m2-selectivity. These examples indicate that a strategy which includes only preliminary in vitro screening may very well preclude the discovery of a novel compound which would prove useful in vivo.
authors.affiliation: Department of Radiology, George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Gitler
authors.forename: S F
authors.initials: SF
authors.lastname: Boulay
authors.forename: V K
authors.initials: VK
authors.lastname: Sood
authors.forename: D W
authors.initials: DW
authors.lastname: McPherson
authors.forename: F F
authors.initials: FF
authors.lastname: Knap
authors.forename: B R
authors.initials: BR
authors.lastname: Zeeberg
authors.forename: R C
authors.initials: RC
authors.lastname: Reba
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D007457:Iodine Radioisotopes; D008024:Ligands; D008297:Male; D011812:Quinuclidines / Q000737:chemistry / Q000378:metabolism; D011813:Quinuclidinyl Benzilate; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate