Smoking Modulates Neuroendocrine Responses to Ipsapirone in Patients with Panic Disorder

Abstract

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients.In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) Neuropharmacological challenges with the selective 5-hydroxytryptamine-1A (5-HT1A) receptor agonist, ipsapirone, have been used in several studies to assess 5-HT1A-receptor related functions in patients suffering from various neuropsychiatric disorders (Broocks et al. 2000;Lesch et al. 1990a;Lesch et al. 1991;Lesch et al. 1990b;Lesch et al. 1992) and in healthy controls (Broocks et al. 1999;Kahn et al. 1994;Lesch et al. 1990c;Lesch et al. 1990d).Indices of abnormal serotonergic function have been reported in patients with panic disorder (PD) and/or agoraphobia (PDA). In particular, there is evidence for an increased sensitivity of the 5-HT 2C subsystem (Charney et al. 1987a;Charney et al. 1987b;Kahn et al. 1988a Kahn and Wetzler 1991;Kahn et al. 1988b). In contrast, stimulation of 5-HT 1A receptors by ipsapirone was followed by an attenuated hypothermic and ACTH/cortisol response in patients with PDA (Broocks et al. 2000;Lesch et al. 1992). In healthy controls, ipsapirone produces dose-dependent increases in plasma cortisol and ACTH as well as dose-dependent reductions in body temperature (Cowen 2001;Kahn et al. 1994;Lesch et al. 1989). Ipsapirone acts on specific serotonergic mechanisms in the brain through its high-affinity binding to the 5-HT 1A receptor subtype. The binding sites are predominantly located on serotonergic neurons in the raphe nuclei (presynaptic autoreceptors) and in limbic structures (postsynaptic receptors). Agonistic properties at presynaptic somatodendritic sites have been observed, resulting in decreased serotonergic neurotransmission (Peroutka 1985). Concerning the high selectivity of ipsapirone, it has to be considered that the metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) has been found to exert antagonistic effects at pre-and postsynaptic ␣ 2-adrenoceptors (Blier et al. 1991;Miller et al. 1992).Several lines of evidence suggest that serotonergic neurotransmission, including the regulation of 5-HT1A receptors, is affected by nicotine (Benwell et al. 1990;Kenny et al. 2001). Recent studies show that some of nicotine's psychotropic and endocrine effects are exerted by stimulation of 5-HT1A receptors on dorsal raphe neurons (Cheeta et al. 2001;Mihailescu et al. 2001).There is a high incidence of smoking in patients with anxiety and other psychiatric disorders (Breslau et al. 1993;Glassman 1993;Kendler et al. 1993;Marks et al. 1997;Miller and Gold 1998;Sellman et al. 1999). To our knowledge, no clinical studies have examined the question of whether psychological or neurobiological effects induced by serotonergic agents such as ipsapi...

Thermal and Microwave-Assisted Synthesis of New Highly Functionalized Bis-β-lactams from Available Compounds via Bisketene as an Intermediate

“…1 − 4 These compounds are widely used in various industries such as pharmaceuticals, food industries, pesticides, and herbicides. 5 − 12 One interesting heterocycle is the four-membered heterocycle of β-lactams, where the ring plays a key and effective role in the action of drugs. 13 − 16 β-Lactams, also called azitidine 2-ones, are quaternary cyclic amides that contain a nitrogen atom attached to a carbonyl group.…”

“…The importance of heterocyclic compounds has been known to humans for a long time, so the synthesis of this family of compounds has been on the agenda of many chemists and pharmacists. Various articles about the preparation and application of heterocyclic compounds are published in the literature every day. − These compounds are widely used in various industries such as pharmaceuticals, food industries, pesticides, and herbicides. − One interesting heterocycle is the four-membered heterocycle of β-lactams, where the ring plays a key and effective role in the action of drugs. − β-Lactams, also called azitidine 2-ones, are quaternary cyclic amides that contain a nitrogen atom attached to a carbonyl group. Antimicrobial, antitumor, anti-inflammatory, antiseizure, antibiotic, anticancer, and antiviral properties have been reported for this family. , In addition, the β-lactam ring acts as a synthon for the synthesis of amino acid derivatives, peptides, polyamino alcohols, and esters .…”

Highly Stereoselective Synthesis of Saccharin-Substituted β-Lactams via in Situ Generation of a Heterosubstituted Ketene and a Zwitterionic Intermediate as Potential Antibacterial Agents

“…Ketenes are remarkable for the variety of ways in which they can be prepared − and also for the range of useful products from their reactions with unsaturated compounds. , They have long been known for their unique reactivity in [2 + 2] cycloaddition reactions. , Saccharin, benzisothiazole derivative, is the foundation for many low-calorie and sugar-free products around the world. , It is used as sweeteners, baked goods, jams, chewing gum, canned fruit, candy, dessert toppings, and salad dressings. , It has been used in medicinal chemistry and is a substituent in several drug molecules such as Ipsapirone (Figure ). − …”