CHARACTERIZATION OF IN-VIVO BRAIN MUSCARINIC ACETYLCHOLINE-RECEPTOR SUBTYPE SELECTIVITY BY COMPETITION STUDIES AGAINST (R,S)-[I-125]IQNB

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-pheny]-10,11-dihyro-5H-dibenzo[b,e][1,4]diazepin-11-one (DIBD) and 11-[[4-[4-(diisobutylamino)butyl-1-phenyl]acetyl]-5,11-dihydro -6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (PBID), by correlating the regional inhibition of (R,S)-[I-125]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 vive m2-selectivity is not correlated with the in vitro m2selectivity. 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.