GABAA receptor pharmacology of fluorinated derivatives of the novel sedative-hypnotic pyrazolopyrimidine indiplon

• Published in: European journal of pharmacology 2008-02, Vol.580 (1-2), p.1-11
• Main Authors: WEGNER, Florian, DEUTHER-CONRAD, Winnie, STEINBACH, Jörg, HOEPPING, Alexander, SCHEUNEMANN, Matthias, BRUST, Peter, FISCHER, Steffen, HILLER, Achim, DIEKERS, Michael, STRECKER, Karl, WOHLFARTH, Kai, ALLGAIER, Clemens
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Benzodiazepines - agonists; Benzodiazepines - chemical synthesis; Benzodiazepines - pharmacology; Binding Sites; Biological and medical sciences; Electrophysiology; Fluorine Compounds - chemical synthesis; Fluorine Compounds - pharmacology; Fluorine Radioisotopes; Humans; Hypnotics and Sedatives - chemical synthesis; Hypnotics and Sedatives - pharmacology; Ligands; Medical sciences; Patch-Clamp Techniques; Pharmacology. Drug treatments; Positron-Emission Tomography - methods; Radioligand Assay; Rats; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Structure-Activity Relationship; Thiophenes - agonists; Thiophenes - chemical synthesis; Thiophenes - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.10.016

The function of gamma-aminobutyric acid type A receptors (GABA(A) receptors) is enhanced by various clinically important drugs including benzodiazepines that act on an allosteric site formed at the interface between the alpha and gamma subunits. In contrast to classical benzodiazepines, the novel pyrazolopyrimidine indiplon (N-methyl-N-{3-[7-(thiophene-2-carbonyl)-1,5,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-2-yl]phenyl}acetamide; N-methyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide) demonstrates relative binding selectivity for the alpha1 subunit containing receptor subtypes, which are the most frequently expressed in the mammalian central nervous system. To investigate the pharmacological properties at GABA(A) receptors and to promote the development of alpha1 subunit selective radiotracers for positron emission tomography imaging, we have started with the evaluation of various fluorinated indiplon derivatives. Binding affinities were determined in homogenates from newborn and adult rats suggesting an alpha1 preference of the reference compounds indiplon, zaleplon as well as for all newly synthesized indiplon derivatives. In homogenated cerebellar tissue obtained from adult rat brain, known to primarily express alpha1 containing GABA(A) receptors, the high affinity of the basic indiplon structure was only slightly affected by an elongation of the alkyl substituent of the amide N from methyl (indiplon; K(i) 3.1 nM) via ethyl (2a, N-(2-fluoro-ethyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 5.4 nM) to propyl (2b, N-(3-fluoro-propyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 2.4 nM). Whole cell patch-clamp recordings at neuronal and recombinant GABA(A) receptors indicated that the fluorinated derivatives 2a and 2b have a high potency at alpha1beta3gamma2L isoforms comparable to indiplon (EC(50): 105, 158, and 81 nM, respectively), with 2b displaying the most pronounced efficacy at alpha3beta3gamma2L subtypes. In conclusion, the affinity profiles and functional properties of the newly synthesised fluorinated indiplon derivatives make compounds 2a and 2b suitable for the development of [(18)F]-labelled ligands at GABA(A) receptors containing the alpha1 subunit.