Selective affinity of pirenzepine analogues for subtypes of muscarinic receptors

Pirenzepine (PZ), telenzepine (TZ) and quinuclidinyl xanthene-9-carboxylate (QNX) are antimuscarinic agents containing a tricyclic ring system and a basic side chain that have been reported to have selective affinity for the M/sub 1/ subtype of receptor. They have prepared and examined seven new PZ analogues containing modifications in either the tricyclic ring system, the side-chain, or both. Affinity for M/sub 1/ type receptors was determined by displacement of specifically-bound (/sup 3/H)PZ from rat cerebral cortex homogenates. Affinity for M/sub 2/ type receptors was measured on rat heart homogenate using (/sup 3/H)(-)quinuclidinyl benzilate. The ratio of the K/sub i/'s for M/sub 1/ and M/sub 2/ receptors were calculated and compared to PZ. All of the compounds had a higher affinity for M/sub 1/ than M/sub 2/ receptors. Three of the compounds were comparable to PZ in selectivity, but the more selective compounds had a weaker affinity for M/sub 1/ receptors. TZ and QNX were less selective than PZ.