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. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.

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Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125-4.0 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.

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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 (K; < 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.Corticotropin releasing factor (CRF) is a 41-amino acid peptide initially identified as a hypothalamic factor responsible for stimulating corticotropin (ACTH) secretion from the anterior pituitary (1, 2). CRF causes a rapid increase in plasma ACTH and glucocorticoid levels when given intravenously (3). Activation of the hypothalamic-pituitary-adrenal (HPA) axis can also result from release of CRF from the paraventricular nucleus of the hypothalamus in response to various stressors (1, 4). In the central nervous system, both CRF-like immunoreactivity and high affinity CRF receptors are heterogeneously distributed in the brain (5, 6). Characterizations of these extrahypothalamic CRF systems demonstrate that, in parallel with its actions on the HPA axis, CRF also acts as a neurotransmitter or neuromodulator to coordinate stress-induced neural responses in the brain (7,8).Intracerebroventricular administration of CRF to rats leads to a constellation of neurochemical, neurophysiological, and behavioral sequelae that include activation of central noradrenergic systems and enhancement of behavioral responses to external stimuli (9-13). In this regard, increases in norepinephrine turnover (10) and in the firing rate of locus coeruleus neurons (13) have been observed following CRF injection. Physiological stressors such as nitroprusside infusions also increase locus coeruleus neuronal firing, an effect blocked by a CRF antagonist (a-helical CRF9-41) and consequently thought to be mediated by endogenous CRF (14,15). The response to hemodynamic stress in this case can be desensitized by chronic treatment with tricyclic antidepressants, suggesting that one possible mode of action of antidepressants might be to alter central CRF neurotransmission (16). In behavioral paradigms, CRF injection i.c.v. produces anxiogenic-like effects in several rodent models (e.g. 17-20). These effects are antagonized by central infusion of peptide antagonists (a-helical CRF9-41 and D-Phe CRF12-41), suggesting the involvement of CRF in anxiety and the utility of CRF antagonists as anxiolytics. The persistence ofbehavioral activation in hypophysectomize...