title: [3H]GR205171 displays similar NK1 receptor binding profile in gerbil and human brain.
abstract: 1 In this study, [(3)H]GR205171 (3(S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine), a potent and selective NK1 receptor antagonist, was characterised in autoradiographic studies in gerbil brain and in binding experiments on homogenates from gerbil and human brain cortex and striatum. 2 In autoradiographic studies in gerbil brain, highest levels of [(3)H]GR205171 binding sites were observed in caudate putamen, nucleus accumbens, medial and cortical nuclei of the amygdala and intermediate levels were detected in the hypothalamus, basolateral amygdala, septum, and cortex. 3 Saturation experiments in homogenates of brain striatum from gerbil showed that [(3)H]GR205171 binds to a single receptor population with a pK(d) value of 10.8+/-0.2 and a B(max) value of 607+/-40 fmol mg(-1). A lower number of NK1 receptor sites was found in cortex, where a B(max) of 94+/-6 fmol mg(-1) protein was obtained. Saturation experiments performed on homogenates from brain striatum of two human subjects and brain cortex of three human subjects showed that [(3)H]GR205171 binds with pK(d) values not different from gerbil and B(max) values ranging from 318+/-51 to 432+/-27 fmol mg(-1) protein in striatum and from 59+/-1 to 74+/-21 fmol mg(-1) protein in cortex. The natural ligand [(3)H]Substance P (SP) bound with sub-nanomolar affinity to 15 and 6% sites compared to [(3)H]GR205171 in gerbil and human striatum, respectively. 4 In competition binding experiments, GR205171 and the NK1 receptor antagonists aprepitant (MK-869), L-733,060 and NKP-608 bound with similar pK(i) values in gerbil and human striatum, irrespective of the use of [(3)H]GR205171 or [(3)H]SP as radioligand. The following rank order was found in terms of pK(i) values: GR205171>aprepitant> or =L-733,060>NKP-608. In homologous displacement experiments in gerbil and human striatum, SP showed nanomolar affinity, whereas in [(3)H]GR205171 competition experiments SP bound with pIC(50) values in the micromolar range and Hill slopes significantly lower than one. 5 It is concluded that the similarities of [(3)H]GR205171 binding characteristics and pharmacology between gerbil and human in cortex and striatum support the use of gerbil in preclinical models to study the effects of NK1 receptor antagonists in the central nervous system.
authors.affiliation: Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Group, Medicines Research Centre, 37135 Verona, Italy. Cristiana.2.Griffante@gsk.com
authors.forename: Cristiana
authors.initials: C
authors.lastname: Griffante
authors.forename: Renzo
authors.initials: R
authors.lastname: Carletti
authors.forename: Filippo
authors.initials: F
authors.lastname: Andreetta
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
mesh_terms: D000293:Adolescent; D000369:Aged, 80 and over; D000818:Animals; D000077608:Aprepitant; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D005260:Female; D005849:Gerbillinae; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D009025:Morpholines / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism*; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000032:analysis / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism*; D014316:Tritium
chemical_list: D008024:Ligands; D009025:Morpholines; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; D014316:Tritium; D000077608:Aprepitant; D013373:Substance P; C103207:vofopitant