cp-99994 and vofopitant

The aim of the present study was to determine the role of tachykinin in the micturition reflex in guinea pigs. We investigated the effects of tachykinin NK(1) receptor antagonists, GR205171 ([2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine), CP99994 ((+), (2R, 3R)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine) and FK888 (N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), the tachykinin NK(2) receptor antagonist, SR48968 ((+)-N-methyl-[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichloro-phenyl)butyl] benzamide), and the tachykinin NK(3) receptor antagonist, SB223412 ((S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide) on rhythmic bladder contraction. GR205171 and CP99994 but not SR48968 or SB223412 reduced bladder contraction frequency. FK888 inhibited the frequency very slightly at the highest dose tested. The distribution of tachykinin NK(1) receptor antagonists to the central nervous system after intravenous administration was examined using an ex vivo binding assay. GR205171 was distributed to the brain and spinal cord, but the tachykinin NK(1) receptor antagonist, FK888, was not. These results suggest that tachykinin NK(1) receptors, which are located in the central nervous system, play an important role in micturition in guinea pigs.

Topics: Animals; Brain; Catheterization; CHO Cells; Cricetinae; Dipeptides; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Indoles; Injections, Intravenous; Iodine Radioisotopes; Male; Muscle Contraction; Muscle, Smooth; Neurokinin-1 Receptor Antagonists; Piperidines; Radioligand Assay; Receptors, Neurokinin-1; Spinal Cord; Substance P; Succinimides; Tetrazoles; Tissue Extracts; Transfection; Urinary Bladder; Urination

The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.

Topics: Animals; Animals, Newborn; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Buspirone; Diazepam; Dose-Response Relationship, Drug; Female; Fluoxetine; Gene Deletion; Guinea Pigs; Imipramine; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Motor Activity; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Social Isolation; Stress, Psychological; Substance P; Tetrazoles; Vocalization, Animal

It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitution at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

Topics: Administration, Oral; Animals; Antiemetics; Cisplatin; Dogs; Dose-Response Relationship, Drug; Ferrets; Humans; Male; Motor Activity; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Shrews; Stereoisomerism; Tetrazoles