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...

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The synthesis of a series of alkylcarbamates of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol is reported. Many of these compounds are potent acetylcholinesterase (AChE) inhibitors. The in vitro AChE inhibition, cholinergic effects, acute toxicity, and elevation of brain acetylcholine levels in vivo of this series of compounds are described. A representative compound, 1d (5.6 mg/kg, po), was able to reverse hemicolinium-3-induced amnesia in the mouse passive avoidance assay.

The synthesis of a series of 1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole 5-alkylcarbamates and their resolution are reported. These compounds are structurally related to physostigmine with substitution of a methylene group in place of the NMe group at position 8 of physostigmine. Many of these 8-carbaphysostigmine analogues are more potent acetylcholinesterase inhibitors in vitro and less toxic in vivo than physostigmine. The (-)-enantiomer (e.g., 1d and 1g) possessing the same absolute configuration at C3a and C8a as that of physostigmine, is about 6 to 12-fold more potent at inhibiting acetylcholinesterase than the corresponding (+)-enantiomer (e.g., 1e and 1h).

Syntheses, Resolution, and Structure-Activity Relationships of Potent Acetylcholinesterase Inhibitors: 8-Carbaphysostigmine Analogues.-Oximation of (I) followed by reductive ring closure and consecutive reduction of both carbonyl groups produces (II). The racemic mixture can be resoluted by means of fractionated crystallization. Alkylation of chiral (II) yields N-alkyl derivatives such as (IV) which are demethylated and treated with isocyanates such as (V) to give the title compounds. (VI) and the n-hexyl analogue are more potent acetylcholinesterase inhibitors than physostigmine but have reduced toxicity. -(CHEN, Y. L.; NIELSEN, J.; HEDBERG, K.; DUNAISKIS, A.; JONES, S.; RUSSO, L.; JOHNSON, J.; IVES, J.; LISTON, D.; J.