ABSTRACT
We here report on a new HLA-A19 allele (A*2416) found in a German kidney recipient. Serological class I typing revealed HLA-A11,19 without clear definition of the A19 split antigen. As with serology, polymerase chain reaction (PCR)-based typing also revealed inconclusive results. We therefore sequenced the gene from the 5' flanking region through the 3'-end of exon 4 of this allele after haplotype-specific PCR amplification. The sequence analysis revealed a new HLA-A allele which is identical to A*3101 with the exception of the 3' half of exon 2 which is identical to the common A9 alleles. The phylogenetic analysis constructed with the nearest-neighbor algorithm and based on exons 1-4 or introns 1-3 clearly indicated, that A*2416 belongs unequivocally to the A19 lineage.
Subject(s)
Alleles , HLA-A Antigens/genetics , Base Sequence , DNA, Complementary , HLA-A Antigens/classification , Humans , Molecular Sequence DataABSTRACT
Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (Ki < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.
Subject(s)
Adrenocorticotropic Hormone/metabolism , Cerebral Ventricles/physiology , Corticotropin-Releasing Hormone/pharmacology , Locus Coeruleus/physiology , Neurons/physiology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Reflex, Startle/drug effects , Acoustic Stimulation , Adenylyl Cyclases/metabolism , Adrenocorticotropic Hormone/blood , Animals , Binding, Competitive , Callithrix , Cell Line , Cell Membrane/enzymology , Cerebral Cortex/enzymology , Cerebral Ventricles/drug effects , Corticotropin-Releasing Hormone/administration & dosage , Dogs , Guinea Pigs , Humans , Injections, Intraventricular , Kinetics , Male , Neurons/drug effects , Pituitary Gland/enzymology , Pyrimidines/administration & dosage , Pyrimidines/metabolism , Pyrroles/administration & dosage , Pyrroles/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitorsABSTRACT
CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2 -phenylpiperidine] interacts with high affinity (pIC50 = 9.8) at the human NK1 receptor expressed in IM-9 cells. In the presence of CP-122,721, there was a reduction in Bmax of [125I]BH-SP binding with no change in affinity suggesting that CP-122,721 does not interact with the NK1 receptor in competitive manner. In an in vitro functional assay. CP-122,721 blocked SP-induced excitation of locus ceruleus cells in guinea pig brain slices with a IC50 value of 7 nM. In vivo, CP-122,721 potently blocked plasma extravasation in guinea pig lung elicited by aerosolized capsaicin (1 mM) with an ID50 = 0.01 mg/kg, p.o. Orally administered CP-122,721 antagonized Sar9, Met (O2)11-SP-induced locomotor activity in guinea pigs with an ID50 = 0.2 mg/kg suggesting good entry into the central nervous system. In addition, consistent with insurmountable blockade observed in vitro, CP-122,721 (0.01, 0.03 0.3 mg/kg, p.o.) produced a rightward shift in the dose response curve for SP-induced hypotension in the awake dog that was accompanied by a decrease in the maximal response. Thus, in vitro and in vivo CP-122,721 appears to behave functionally as a non-competitive antagonist producing an insurmountable blockade of the actions of SP.
Subject(s)
Neurokinin-1 Receptor Antagonists , Piperidines/pharmacology , Animals , Blood Pressure/drug effects , Capillary Permeability/drug effects , Dogs , Female , Guinea Pigs , Humans , Locus Coeruleus/drug effects , Male , Motor Activity/drug effects , Piperidines/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Neurokinin-1/metabolism , Salivation , Substance P/antagonists & inhibitorsABSTRACT
N-demethylation of the selective serotonin reuptake inhibitor sertraline to desmethylsertraline yields a compound with 10- to 20-fold less potency at blocking serotonin (5-HT) reuptake as measured in vitro. In the present study desmethylsertraline (DMS) was examined in two in vivo models of reuptake inhibition--elevation of extracellular 5-HT in the corpus striatum as measured by microdialysis and inhibition of firing of serotonin-containing dorsal raphe neurons. Whereas sertraline (1, 3.2, and 10 mg/kg s.c.) produced a dose-dependent increase in extracellular 5-HT and a decrease in 5-HIAA in rat striatum, desmethylsertraline was without effect on either parameter. In similar fashion, desmethylsertraline had no effect on dorsal raphe cell firing at a dose (1,000 micrograms/kg i.v.) nearly 20-fold the ED50 for sertraline (52 micrograms/kg). Taken together, these data suggest that DMS does not contribute to the blockade of central 5-HT reuptake produced by sertraline in vivo and therefore would be expected to play a negligible role in its clinical activity.
Subject(s)
1-Naphthylamine/analogs & derivatives , Receptors, Serotonin/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , 1-Naphthylamine/metabolism , 1-Naphthylamine/pharmacology , Animals , Dose-Response Relationship, Drug , Male , Raphe Nuclei/drug effects , Rats , Rats, Sprague-Dawley , Sertraline , Time FactorsABSTRACT
The synthesis of a highly potent and selective NK1 receptor antagonist radioligand, [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine (6a) is described. The in vitro binding pharmacology and autoradiographic distribution of 6a in guinea pig brain following peripheral administration are also reported.
Subject(s)
Neurokinin A/antagonists & inhibitors , Neurokinin-1 Receptor Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacology , Amino Acid Sequence , Animals , Autoradiography , Brain/metabolism , Guinea Pigs , Male , Molecular Sequence Data , Piperidines/metabolism , Radioligand Assay , Stereoisomerism , Substance P/chemistrySubject(s)
Neurokinin A/antagonists & inhibitors , Neurokinin-1 Receptor Antagonists , Piperidines/pharmacology , Albuterol/pharmacology , Animals , Binding, Competitive , Calcium Channels/drug effects , Calcium Channels/metabolism , Capsaicin/pharmacology , Dose-Response Relationship, Drug , Guinea Pigs , Kinetics , Lung/drug effects , Lung/physiology , Piperidines/metabolism , Receptors, Neurokinin-1/metabolism , Receptors, Neurokinin-1/physiology , Thiorphan/pharmacology , Verapamil/analogs & derivatives , Verapamil/metabolismABSTRACT
The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.
Subject(s)
Biphenyl Compounds/pharmacology , Calcium Channels/drug effects , Receptors, Neurotransmitter/antagonists & inhibitors , Substance P/metabolism , Animals , Binding, Competitive , Brain/drug effects , Diltiazem/pharmacology , Drug Interactions , Guinea Pigs , Heart/drug effects , Nitrendipine/pharmacology , Radioligand Assay , Rats , Receptors, Neurokinin-1 , Tritium , Verapamil/analogs & derivatives , Verapamil/pharmacologyABSTRACT
The design and synthesis of a series of potential atypical antipsychotic agents based on the structure of 1-naphthylpiperazine are described. The incorporation of dopamine antagonist activity into the parent structure was achieved with heterocyclic surrogates for the catechol moiety of dopamine. Compound 4b from this series showed a biochemical profile that translated to behavioral activity in the rat predictive of an antipsychotic agent with a low propensity to cause extrapyramidal side effects in man.
Subject(s)
Antipsychotic Agents , Piperazines/pharmacology , 8-Hydroxy-2-(di-n-propylamino)tetralin , Amphetamines/pharmacology , Animals , Apomorphine/pharmacology , Autoradiography , Behavior, Animal/drug effects , Dopamine Antagonists , Haloperidol/pharmacology , Ketanserin/metabolism , Locomotion/drug effects , Male , Prazosin/metabolism , Rats , Rats, Inbred Strains , Structure-Activity Relationship , Tetrahydronaphthalenes/metabolismABSTRACT
CP-96,345, a nonpeptide substance P antagonist, is selective for the tachykinin NK1 receptor. The compound binds to a single population of sites in guinea pig brain and potently inhibits substance P-induced excitation of locus ceruleus neurons. CP-96,345 should be a useful tool for studying the action of substance P in the central nervous system.
Subject(s)
Biphenyl Compounds/metabolism , Brain/metabolism , Corpus Striatum/metabolism , Receptors, Neurotransmitter/antagonists & inhibitors , Receptors, Neurotransmitter/metabolism , Action Potentials , Animals , Autoradiography , Binding Sites , Binding, Competitive , Biphenyl Compounds/pharmacology , Brain/diagnostic imaging , Corpus Striatum/diagnostic imaging , Guinea Pigs , Hydrogen-Ion Concentration , Male , Radionuclide Imaging , Receptors, Neurokinin-1 , Receptors, Tachykinin , Spectrophotometry , Substance P/metabolism , Tachykinins/metabolismABSTRACT
A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.