clozapine and perlapine

Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

Topics: Acetylcholine; Animals; Cholinergic Agonists; Clozapine; Designer Drugs; Dibenzazepines; Humans; Ligands; Receptor, Muscarinic M3; Serotonin Antagonists; Signal Transduction; Structure-Activity Relationship

Six dibenzo-azepine derivatives were compared for their effects on suppressed and nonsuppressed behavior of squirrel monkeys. Monkeys responded by pressing a lever under a two-component fixed-ratio schedule of food presentation in which responding in one component was suppressed by response-produced electric shock. Intermediate doses (0.3-1.0 mg/kg IM) of selected unsubstituted and 8-chlorine-substituted dibenzo-azepines (perlapine, 106-094, and clozapine) increased responding that was suppressed by electric shock, whereas selected 2-chlorine-substituted dibenzo-azepines (loxapine, clothiapine, and 105-056) did not consistently increase suppressed responding at any dose (0.001-0.1 mg/kg IM). All six dibenzo-azepines decreased nonsuppressed responding in a dose-related manner, with the 2-chlorine-substituted derivatives being 16-50 times more potent than their unsubstituted or 8-chlorine-substituted congeners. These structure-activity relationships indicate that the effects of the dibenzo-azepines on both suppressed and nonsuppressed behavior differ qualitatively depending on the location of the chlorine substituent.

Topics: Animals; Behavior, Animal; Clozapine; Dibenzazepines; Dibenzothiazepines; Inhibition, Psychological; Loxapine; Male; Saimiri; Structure-Activity Relationship

The presence of specific, stereo-selective octopamine receptors has been demonstrated in the non-spontaneously beating accessory ventricle (aortic bulb) of the clam Tapes watlingi. Analogues of octopamine with a single chloro group in either the para or meta positions of the benzene ring were 10 times less potent than octopamine in their agonist activity. In low concentrations (less than 200 microM), phentolamine, chlordimeform and clozapine were octopamine antagonists. In high concentrations (greater than 200 microM), clozapine, clonidine and chlordimeform induced changes in aortic tone similar to that produced by p-octopamine. This activity may result from the chloro-substituted phenamidine skeleton in both clozapine and chlordimeform.

Topics: Action Potentials; Amidines; Animals; Bivalvia; Chlorphenamidine; Clozapine; Curare; Dibenzazepines; Dopamine; Heart; Myocardial Contraction; Octopamine; Receptors, Adrenergic; Receptors, Biogenic Amine; Receptors, Dopamine; Serotonin

1. The anti-dopaminergic effects of several dibenzodiazepines were examined on the dopamine-stimulated adenylate cyclase in rat striatal homogenates. The "cis" isomer of clozapine, HF-2046, was the most potent in this respect and perlapine, which is devoid of neuroleptic activity, was the weakest. 2. The anti-muscarinic effects of the same compounds were measured by using the muscarinic affinity label 3H-propylbenzilylcholine mustard. HF-2046 was the most potent and loxapine the least potent of the drugs used. 3. The anti-dopaminergic effects of the drugs correlate well with neuroleptic but not with extrapyramidal effects. The anti-dopaminergic/anti-muscarinic ratio, however, correlates well with extrapyramidal rather than neuroleptic effects.

Topics: Adenylyl Cyclases; Animals; Cerebral Cortex; Choline; Clozapine; Corpus Striatum; Dibenzazepines; Dibenzothiazepines; Dopamine Antagonists; Homovanillic Acid; Loxapine; Male; Parasympatholytics; Parkinson Disease, Secondary; Piperazines; Rats; Receptors, Cholinergic