Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.

Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts.

Age-associated synapse elimination in mouse parasympathetic ganglia.

Little is known about the effects of aging on synapses in the mammalian nervous system. We examined the innervation of individual mouse submandibular ganglion (SMG) neurons for evidence of age-related changes in synapse efficacy and number. For approximately 85% of adult life expectancy (30 months) the efficacy of synaptic transmission, as determined by excitatory postsynaptic potential (EPSP) amplitudes, remains constant.

HLA-A*2416: a new allele of the HLA-A19 lineage.

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.

CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.

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.

Characterization of CP-122,721; a nonpeptide antagonist of the neurokinin NK1 receptor.

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.

Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo.

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.

Synthesis, in vitro binding profile, and autoradiographic analysis of [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine, a highly potent and selective nonpeptide substance P receptor antagonist radioligand.

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.

The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels.

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.

1-Naphthylpiperazine derivatives as potential atypical antipsychotic agents.

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.

Activity and distribution of binding sites in brain of a nonpeptide substance P (NK1) receptor antagonist.

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.

Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists.

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).

3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one: a potent and selective serotonin (5-HT1B) agonist and rotationally restricted phenolic analogue of 5-methoxy-3-(1,2,5,6-tetrahydropyrid-4-yl)indole.

The synthesis and in vitro and in vivo characteristics of 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1, CP-93,129) are described. This rotationally restricted phenolic analogue of RU-24,969 is a potent (15 nM) and selective (200x vs the 5-HT1A receptor, 150x vs the 5HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regulating feeding behavior in rodents.

Pharmacology of sertraline: a review.

Sertraline is a member of a new class of psychotherapeutic agents that selectively inhibit serotonin reuptake in the brain. Animal studies have demonstrated that inhibition of serotonin reuptake leads to enhanced serotonergic neurotransmission and indirectly results in a down-regulation of beta-adrenoceptors. The preclinical pharmacology of sertraline predicts antidepressant activity without accompanying anticholinergic, cardiotonic, or sedative side effects.

Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: evidence from single unit studies in freely moving cats.

Although central serotonergic systems appear to be linked importantly to the mechanism of action of a variety of hallucinogenic drugs, the nature of this interaction has remained unclear. In the present study, the question of whether the critical link is presynaptic or postsynaptic was examined in cats. Behaviorally inactive doses (1.

Activity of serotonin-containing neurons in nucleus centralis superior of freely moving cats.

Serotonergic neurons were recorded in the nucleus centralis superior (NCS) in freely moving cats and were initially identified on-line by their slow and regular spontaneous activity (mean 2.55 +/- 0.21 spikes/s).

Chloral hydrate anesthesia alters the responsiveness of central serotonergic neurons in the cat.

The influence of chloral hydrate anesthesia on the spontaneous activity and responsiveness of serotonergic neurons was examined by administering chloral hydrate (300 mg/kg, i.p.) to freely moving cats from which serotonergic unit activity in the dorsal raphe nucleus (DRN) was being recorded.

Raphe unit activity in freely moving cats is altered by manipulations of central but not peripheral motor systems.

Single unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats was recorded in experiments which manipulated central or peripheral motor systems. Unilateral microinjections of the cholinomimetic agent, carbachol, into the pontine tegmentum, produced muscle atonia. During these periods of drug-induced atonia, the activity of serotonergic neurons was reduced 97% below pre-drug baseline rates.

Response of dopaminergic neurons in cat to auditory stimuli presented across the sleep-waking cycle.

The response of dopaminergic neurons of the substantia nigra pars compacta to auditory clicks continuously presented across the sleep-wake cycle was studied in cats. The initial excitatory followed by inhibitory response to the click which occurred during quiet waking diminished as the cat progressed into slow-wave sleep and was absent during REM sleep. Upon awakening from REM sleep, dopamine neurons once again displayed an excitatory/inhibitory response to the clicks, implying that the decrease across the sleep-wake cycle was not attributable to long-term habituation.

Raphe neurons: firing rate correlates with size of drug response.

Significant negative correlations were obtained between the spontaneous discharge rate during waking and the neural response to systemic injections of either 5-MeODMT or LSD for serotonergic neurons in the dorsal raphe nucleus, nucleus centralis superior, and nucleus raphe pallidus of unanesthetized and unrestrained cats. These data are discussed in terms of an hypothesis which accounts for both the rate of spontaneous activity of serotonergic neurons and the magnitude of their response to serotonin agonist drugs in terms of autoreceptor density on individual neurons.

Behavioral correlates of dopaminergic unit activity in freely moving cats.

Single unit activity of dopaminergic neurons in the substantia nigra was recorded in freely moving cats under a variety of conditions. These neurons displayed their highest discharge rate during active waking (3.68 +/- 0.